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, brain injury and / or brain injury comprising a combination of (i) omega-3 fatty acid DHA, and (ii) vitamin B2, and (iii) vitamin D3, and one or more from (iv) choline or salts and / or esters thereof and (v) dietary fibers and / or dietary butyrates. The invention also relates to a composition comprising a combination of DHA, vitamin B2, vitamin D3, and one or more from (iv) choline or salts and / or esters thereof, and (v) dietary fibers and / or dietary butyrates.

Description

TECHNICAL FIELD

[0001] The present invention is in the field of compositions and nutritional compositions for use in the treatment of neurodegenerative diseases, preferably in the treatment and / or amelioration of symptoms of neurodegenerative diseases, and their use in neurotrauma / brain trauma and / or functional recovery after brain damage and / or amelioration of neurological impairment caused by trauma. BACKGROUND

[0002] Neurite outgrowth refers to the process by which nerve cells, also known as neurons, extend their processes called neurites. Neurites include both axons and dendrites. Axons transmit electrical or neurochemical signals to other neurons, while dendrites receive signals from adjacent neurons.

[0003] When neurons undergo neurite outgrowth, they are enabled to establish connections and communicate with other neurons in the brain. These connections are essential for brain function and form what are called functional connections. Functional connections refer to the patterns of communication and interaction between different brain regions, involving 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 towards specific target zones and seek out other neurons or brain regions to form connections, allowing the establishment of neural circuits and enabling information processing and transmission. The growth of neurites contributes to the formation of synapses, which are the points of connection between neurons, thus contributing to the overall functional connectivity of the brain. The complex network of neurons is responsible for various brain functions, including sensory perception, motor control, sleep, memory, and cognitive processes, by sending and receiving signals.

[0005] Neurodegenerative diseases can disrupt the functional connectivity of the brain 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 and maintain functional connectivity in the brain. This collectively leads to progressive decline in brain function and characteristic symptoms associated with these diseases, such as memory loss, motor difficulties, sleep disturbances, and cognitive impairment.

[0006] Treatment of neurodegenerative diseases focuses on medication, delaying disease progression, 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 down disease progression.

[0007] CN107889992 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 comprises vitamins and trace elements. WO 2021 / 034942 describes a dietary supplement to improve dietary insufficiencies associated with brain health or neurodegenerative diseases, which contains two polyphenol compounds, omega-3 fatty acids, water-soluble and oil-soluble vitamin components and magnesium. CN112890136 describes an antioxidant total nutrient powder as an adjuvant therapy for treating Alzheimer’s disease, which comprises DHA, B vitamins, vitamin D, phospholipids and taurine, among many other ingredients. WO 2018 / 226089 focuses on treating impaired motor skills in mammals suffering from Parkinson’s disease (PD), and mentions the presence of omega-3 fatty acids, choline and D3, and relates to the neuroprotective effect of dietary fiber in PD patients.

[0008] Neurotrauma refers to an 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. Traumatic brain injury (TBI) occurs when the head is suddenly jolted, shaken, or subjected to a penetrating injury, resulting in disruption of normal brain function. TBIs can range from mild concussions to severe injuries that result in long-term or permanent neurological deficits. SCI refers to damage to the spinal cord that results in loss of motor and sensory function below the level of injury. Depending on the location and severity of the injury, SCI can result in varying degrees of paralysis. Peripheral nerve injury involves damage to nerves located outside the brain and spinal cord. These injuries can occur due to trauma, such as lacerations, fractures, or compression, and can result in loss of sensory or motor function in the affected area. Neurotrauma can have significant consequences and can result in physical, cognitive, and psychological impairments. In this regard, depending on the severity and type of injury, neurotrauma can have direct and indirect effects on neurite outgrowth.

[0009] Several ways in which a neural trauma can affect neurite outgrowth are: disruption / disconnection of neuronal structures, including axons and dendrites; axonal degeneration, which results in retraction or loss of axonal processes; excessive or chronic inflammation can inhibit neurite outgrowth; scar tissue formation at the site of injury can create a physical barrier that hinders the extension of neuronal processes; changes in the cellular environment via the release of inflammatory molecules, excitotoxicity, and changes in neurotransmitter balance, which affect neurite outgrowth by affecting the availability of growth factors and appropriate guidance cues necessary for proper neuronal development and regeneration. In some cases, however, neuronal regeneration can occur, in which damaged or interrupted axons grow again. The extent and success of regeneration depend on a variety of factors, including age, overall health, severity of the injury, presence of inhibitory factors in the environment, and the ability of the damaged neurons to grow again.

[0010] WO 2012125034 describes a composition comprising: i) one or more of: uridine and cytidine, or a salt, phosphate, acyl derivative or ester 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 an ester thereof, wherein the lipid fraction comprises less than 2% by weight of a-linolenic acid (ALA) based on the weight of all fatty acids; iii) choline, or a salt or ester thereof; for use in the prevention or treatment of neural trauma TBI, cerebral palsy and SCI.

[0011] 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 a traumatic brain injury, comprising enterally administering to the subject a composition comprising a therapeutically effective amount of: (i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative or ester thereof; (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 vitamins B6, B9 and B12. US 20170127693 describes a nutritional composition for pediatric use comprising butyrate, DHA, phosphatidylcholine, the recommended daily amount of vitamins D and B2, but does not mention the addition of dietary fiber or the neurological application of the composition.

[0012] WO 2016014473 describes a composition comprising human milk oligosaccharides (or precursors) and mentions a formulation further comprising DHA, vitamin B2 and vitamin D3 among other ingredients. It mentions various uses, among which neurodegenerative diseases are mentioned, but no neurotrauma or brain injury, and also no mention of the presence of phosphatidylcholine.

[0013] WO 2019165222 describes daily nutritional supplements for kidney disease containing higher than recommended daily amounts (RDA) of vitamin B2 and D3 levels. It is indicated that the supplements can be added with omega 3 fatty acids. It does not mention choline and dietary fiber, nor neurotrauma and brain injury (as therapeutic applications).

[0014] EP 2342975 describes a composition for the treatment of Alzheimer's disease containing omega-3 fatty acids, protein, manganese or molybdenum, vitamin B2, vitamin D3 and choline, but it does not mention dietary butyrate or phosphatidylcholine. It is indicated that the presence of vitamins B6, B9 and B12 can exceed the human RDA, but the amounts of vitamins B2 and D are added only in amounts matching the RDA.

[0015] Current dietary options include many different nutrients, however those nutrients show mixed results in different combinations of nutrients. Therefore, there is still a need to provide a method to find a nutritional supplement or nutritional composition to treat neurodegenerative diseases and neurotrauma. SUMMARY

[0016] The inventors surprisingly found that a composition comprising a therapeutically effective amount of a combination of omega-3 fatty acid docosahexaenoic acid (DHA), vitamin B2 and vitamin D3 is effective in the treatment of neurodegenerative diseases, neurotrauma and brain injury / brain damage. The treatment of neurodegenerative diseases includes the treatment of symptoms of these neurodegenerative diseases, as well as the treatment of neurotrauma (including neurotrauma caused by external factors). The treatment of brain injury / brain damage includes the improvement of neural recovery after brain injury or damage has occurred.

[0017] Surprisingly, a composition was developed comprising a limited number of ingredients acting in a synergistic way. It was found that this composition reduces the risk of counteracting mechanisms in neurodegenerative diseases and neurotrauma and / or in brain injury / brain damage, or reduces the risk of unwanted side effects in patients. Without being bound by theory, it is believed that the therapeutically effective amount of omega-3 fatty acid DHA, vitamin B2 and vitamin D3 reduces the effects of oxidative stress and suppresses inflammation, modulates synaptic plasticity and molecular transport in organelles in a synergistic way.

[0018] In an in vitro PC12 model, compositions containing these components resulted in increased neurite outgrowth (as defined by the number and / or length of neurites per cell) compared to compositions lacking ω-3 fatty acid DHA, vitamin B2, and vitamin D3. This increase in neurite outgrowth (the number and / or length of neurites per cell) in PC12 cells was higher than expected based on the additive effect of the individual components, demonstrating a synergistic effect among the three components.

[0019] Further observation revealed that the addition of choline, particularly phosphatidylcholine (PC), to the combination of DHA, B2, and D3 further improved neurite outgrowth, and to a greater extent than expected based on the combined effects of choline or PC alone with the effects of DHA, B2, and D3. A similar super-additive effect was observed when butyrate was supplemented with DHA, B2, and D3. Furthermore, it was found that supplementing PC12 cells with the combination of all five of the aforementioned components unexpectedly led to even further improvement (i.e., increase) in neurite outgrowth compared to the sum of the effects of the individual components, suggesting a synergistic effect of these components in increasing neurite outgrowth.

[0020] The inventors also unexpectedly discovered that a combination of micronutrients containing omega-3 fatty acid DHA, vitamin B2 and vitamin D3, and optionally the addition of choline, particularly phosphatidylcholine (PC) and / or butyrate, has a synergistic effect on the outward growth of neurites.

[0021] Increased neurite outgrowth refers to neurite density, which reflects the number and / or length of neurites per cell, preferably the number and length of neurites per cell. Particularly in the context of brain trauma, increased neurite outgrowth can play a positive role in supporting functional connectivity in the brain and contribute to functional recovery. Any improvement (i.e., increase) in neurite outgrowth, as observed in PC12 cell studies, can lead to improvements in those brain regions affected by trauma. The same principle applies to brain injury and / or brain damage.

[0022] Similarly, increased outward ingrowth density of neurites in neurodegenerative diseases can help compensate for the loss of neuronal connectivity. It allows surviving neurons to extend their neurites and establish new synaptic connections, thus partially restoring functional circuitry. This compensation can help mitigate the effects of neuronal loss and maintain or regain certain aspects of normal brain function, leading to improved prognosis and functional recovery. Furthermore, increased outward ingrowth of neurites can contribute to neural plasticity, which allows surviving neurons to adapt and establish new connections in response to changing environments. This adaptation can help the brain compensate for the loss of specific neuronal populations and maintain functional connectivity, potentially slowing disease progression and improving prognosis.

[0023] Unbound by theory, it is believed that DHA, when administered in conjunction with vitamin D3 and vitamin B2, beneficially reduces oxidative damage, thereby helping to reduce the degree of neuronal damage and support brain metabolism, cell survival, and providing anti-inflammatory effects while supporting the healing or recovery of neuronal damage. Choline is associated with reduced neuroinflammation, functional and structural connectivity, and has a beneficial effect on cerebral blood flow. Dietary fiber and / or dietary butyrate provide butyrate as an alternative cellular energy source and exhibit neuroprotective effects by reducing oxidative stress and inflammation in neurons. It is believed that the components of the compositions according to the invention provide, on the one hand, optimal promotion of outward regrowth and recovery of neurites following neuronal damage, while supporting brain function.

[0024] Therefore, the present invention relates to a method for treating neurodegenerative diseases and / or neurotrauma, the method comprising administering a composition according to the invention to a subject. The invention further relates to a composition for use in treating neurodegenerative diseases and / or neurotrauma, the composition comprising a combination of: i) ω-3 fatty acid DHA, and ii) vitamin B2, and iii) vitamin D3, and iv) choline and / or PC, and v) dietary fiber and / or dietary butyrate, or one or more of these. This invention relates to a method for treating brain injury and / or brain damage, the method comprising administering a composition according to the invention to a subject. The invention further relates to a composition for use in treating brain injury and / or brain damage, the composition comprising a combination of: i) ω-3 fatty acid DHA, and ii) vitamin B2, and iii) vitamin D3, and iv) choline and / or PC, and v) dietary fiber and / or dietary butyrate, one or more of these.

[0025] In some embodiments of the present invention, the dietary fiber is selected from short-chain galacto-oligosaccharides (scGOS), long-chain fructooligosaccharides (lcFOS), and low-viscosity pectin. Therefore, the present invention relates to a composition comprising the following therapeutically effective combination: i) ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate.

[0026] Preferably, the composition according to the invention further comprises one or more selected from vitamins 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) omega-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.

[0027] In another embodiment, the present invention relates to a method for treating a subject with neurodegenerative diseases and / or neurotrauma, the method comprising administering to the subject a composition according to the invention. The invention can also be described as the use of the following therapeutically effective combinations for manufacturing a composition for treating neurodegenerative diseases and / or neurotrauma: i) ω-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, with one or more combinations of iv) choline and / or PC and v) dietary fiber and / or dietary butyrate. Furthermore, the present invention relates to the use of the following therapeutically effective combinations for manufacturing a composition for treating a subject with neurodegenerative diseases and / or neurotrauma: i) ω-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. In other words, the present invention relates to a composition for use in treating neurodegenerative diseases and / or neurotrauma in subjects, the composition comprising i) a combination of ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate.

[0028] In another preferred embodiment, the present invention relates to a method for treating brain injury and / or brain damage in a subject, the method comprising administering to the subject a composition according to the invention. The invention can also be described as the use of the following therapeutically effective combinations for manufacturing a composition for treating brain injury and / or brain damage: i) ω-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, with one or more combinations of iv) choline and / or PC and v) dietary fiber and / or dietary butyrate. Furthermore, the present invention relates to the use of the following therapeutically effective combinations for manufacturing a composition for treating brain injury and / or brain damage in a subject: i) ω-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. In other words, the present invention relates to a composition for use in treating brain injury and / or brain damage in a subject, the composition comprising i) a combination of ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate.

[0029] In embodiments, the present invention relates to the treatment or prevention of symptoms associated with neurodegenerative diseases, including improving outward ingrowth of neurites in treated subjects with said neurodegenerative diseases (e.g., an increase in the number and length of neurites) compared to subjects with neurodegenerative diseases who have not been treated with the compositions according to the present invention. In another embodiment, the present invention relates to the treatment of neurotrauma, including improving outward ingrowth of neurites in treated subjects with neurotrauma (e.g., an increase in the number and length of neurites) compared to subjects who have not been treated with the compositions according to the present invention. In yet another embodiment, the present invention relates to the treatment of brain injury and / or brain damage, including improving outward ingrowth of neurites in treated subjects with brain injury and / or brain damage (e.g., an increase in the number and length of neurites) compared to subjects who have not been treated with the compositions according to the present invention. In alternative embodiments, the present invention relates to the treatment of brain injury and / or brain damage, comprising improving the neurological function (selected from motor, behavioral, emotional, cognitive, and sensory functions) of a treated subject with brain injury and / or brain damage compared to a subject not treated with the compositions according to the invention. In some embodiments, the treatment of neurodegenerative diseases and / or neurotrauma further comprises, i.e., neuroprotection following a diagnosis of neurodegenerative disease or neurotrauma. In other embodiments, the treatment of brain injury and / or brain damage comprises neuroprotection following a diagnosis of said brain injury and / or brain damage.

[0030] This invention relates to the treatment or prevention of symptoms associated with neurodegenerative diseases, including the prevention or improvement of the functional consequences of neurodegenerative diseases.

[0031] In some embodiments, the present invention relates to the treatment of neurodegenerative diseases selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia. In other embodiments, the present invention relates to the treatment or prevention of symptoms associated with neurodegenerative diseases, including, but not limited to, preventing or improving the functional consequences of neurodegenerative diseases, such as, but not limited to: - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform daily activities; and / or - Motor symptoms associated with tremor, rigidity, bradykinesia, coordination, and balance; - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional blunting, social withdrawal, and mood swings; - Sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature; - Sleep disorders associated with insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder; - Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in body temperature regulation.

[0032] In a preferred embodiment, the neurodegenerative disease, as defined herein, is not caused by stroke or ischemic stroke.

[0033] In other embodiments, the present invention relates to the treatment of neurotrauma selected from traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury. In some further embodiments, the present invention relates to the treatment of neurotrauma caused by one or more external factors selected from: - Occupational hazards, including automotive, sports, and workplace accidents; - Explosion and blast damage; -electric shock; - Blunt force trauma; - Penetrating injury, which involves an external object (including a bullet or sharp object) penetrating into the brain, spinal cord, or peripheral nerves.

[0034] In another embodiment, the present invention relates to the treatment of brain injury and / or brain damage, wherein the treatment is selected from improving neurological recovery following brain injury and / or brain damage, preventing and / or reducing the deterioration of neurological damage caused by brain injury and / or brain damage. Neurological recovery and neurological damage as referred to herein are the recovery and impairment of neurological functions of the brain (selected from motor, behavioral, emotional, cognitive, and sensory functions). In another embodiment, the present invention relates to the treatment of brain injury and / or brain damage caused by internal factors selected from: stroke, ischemia, bacterial and / or viral infection, type 1 or type 2 diabetes, acute alcohol poisoning, cancer treatment, and chemotherapy. In a preferred embodiment, the brain injury and / or brain damage is an acute injury, meaning that the injury occurs within a time span of several days from the start of treatment with the composition according to the invention, preferably within 21 days, more preferably within 15 days. In another preferred embodiment, the brain injury and / or brain damage is a localized injury located in a specific or particular region of the brain. In a more preferred embodiment, the present invention relates to the treatment of brain injury and / or brain damage, wherein the brain injury and / or brain damage is a localized and acute injury of the brain.

[0035] In an alternative embodiment, the present invention relates to the treatment of cerebral palsy.

[0036] In a preferred embodiment, the application or use of the composition begins after a diagnosis of neurodegenerative disease or its prodromal period and / or after a neurological injury, and the application or use of the composition lasts for a period of at least 2 weeks, preferably at least 1 month, preferably at least 2 months, more preferably at least 4 months, and even more preferably at least 6 months. In another preferred embodiment, the application or use of the composition begins after a brain injury and / or brain damage, and the application or use of the composition lasts for a period of at least 2 weeks, preferably at least 1 month, preferably at least 2 months, more preferably at least 4 months, and even more preferably at least 6 months. Attached Figure Description

[0037] The invention will now be discussed in more detail with reference to the accompanying drawings. In all figures, the outward growth of neural processes is expressed as a percentage relative to the control (100%).

[0038] Figure 1 The effects of ω-3 fatty acid DHA (6.7 µM), eicosapentaenoic acid (EPA) (10 μM), vitamin B2 (1.25 μM), and vitamin D3 (0.25 μM), and their combinations, on the outward growth of neurites in PC12 neurons were shown.

[0039] Figure 2The effects of combinations of ω-3 fatty acids DHA (6.7 µM), vitamin B2 (0.5 µM), and vitamin D3 (0.25 µM) and combinations of DHA (6.7 µM), vitamin B2 (1 µM), and vitamin D3 (0.25 µM) on the outward growth of neurites in PC12 neurons were shown.

[0040] Figure 3 The effects of combinations of ω-3 fatty acids DHA (3.3 µM), vitamin B2 (0.5 µM), and vitamin D3 (0.25 µM) and combinations of DHA (3.3 µM), vitamin B2 (1 µM), and vitamin D3 (0.25 µM) on the outward growth of neurites in PC12 neurons were shown.

[0041] Figure 4 The effects of choline chloride (20 µM), PC (20 μM), and their molar ratios of 60:40 or 40:60 providing 20 μM choline on the outward growth of neurites in PC12 neurons were shown.

[0042] Figure 5 The effects of choline chloride (20 µM), PC (20 µM), and their combinations with DHA (3.3 µM), vitamin B2 (0.5 μM), and vitamin D3 (0.25 μM) on neurite outgrowth in PC12 neurons were shown. The effects of a combination of choline chloride and phosphatidylcholine (providing 20 μM choline, of which 80 mol% of the total choline is derived from choline chloride and 20 mol% from PC) with DHA, vitamin B2, and vitamin D3 were also shown.

[0043] Figure 6 The effects of combinations of PC (20 µM), DHA (5 µM) and EPA (1 µM), vitamin B2 (0.5 µM) and vitamin D3 (0.25 μM), as well as the effects of PC combined with DHA, EPA, vitamin B2 and vitamin D3, on the outward growth of neurites in PC12 neurons were shown.

[0044] Figure 7 The effects of different concentrations of butyric acid (BA) on the outward growth of neurites in PC12 neurons were shown.

[0045] Figure 8The effects 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 neurons were shown. The effects of combinations of DHA, vitamin B2, and D3, combinations of DHA, vitamin B2, and D3 with BA or PC, and combinations of all nutrients BA, DHA, PC, vitamin B2, and D3 were also shown.

[0046] Figure 9 The effects of vitamin B2 (0.25 µM), vitamin D3 (0.75 µM), PC (15 µM), and BA (40 µM) alone on neurite outgrowth in PC12 neurons were shown. The effects of a reference diet containing PC (5 µM), DHA (2 µM), choline chloride (4 µM), vitamin C (15 µM), vitamin E (4 µM), vitamin B6 (2 µM), vitamin B9 (3 µM), vitamin B12 (0.02 µM), and selenium (0.016 µM) were also shown. Combinations of the reference diet with additional supplementation of vitamin B2 (0.25 µM), vitamin D3 (0.75 µM), PC (15 µM), and BA (40 µM) were further shown.

[0047] Figure 10 The effects of vitamin B2 (0.25 µM), vitamin D3 (0.75 µM), and BA (200 µM) alone on neurite outgrowth in PC12 neurons were shown. The effects of a reference diet containing PC (5 µM), DHA (2 µM), choline chloride (4 µM), vitamin C (15 µM), vitamin E (4 µM), vitamin B6 (2 µM), vitamin B9 (3 µM), vitamin B12 (0.02 µM), and selenium (0.016 µM) were also shown. Combinations of the reference diet with additional vitamin B2 (0.25 µM), vitamin D3 (0.75 µM), and BA (200 µM) were further shown.

[0048] Figure 11 The study shows the mNSS (modified neurological injury severity score) scores of three study groups over a 7-week time span at baseline (BL) and postoperatively. These study groups consisted of: a sham injury group given a control diet, a brain injury group given a control diet, and a brain injury group given an active diet.

[0049] Figure 12The results of foot slip tests 51 days post-surgery were shown for three study groups: a sham injury group given a control diet, a brain injury group given a control diet, and a brain injury group given an active diet.

[0050] List of preferred embodiments 1. A nutritional composition comprising the following therapeutically effective combination: i) ω-3 fatty acids, wherein the ω-3 fatty acids contain at least DHA; ii) Vitamin B2; and iii) Vitamin D3, and one or more of the following: iv) choline or its salts and / or phosphatidylcholine; and v) Dietary fiber and / or dietary butyrate, This nutritional composition is intended for use in the treatment of neurodegenerative diseases and / or neurotrauma and / or cerebral palsy, preferably for use in the treatment of neurodegenerative diseases and / or neurotrauma, brain injury and / or brain damage and / or cerebral palsy.

[0051] 2. The nutritional composition for use according to Example 1, wherein at least 40 mol% of choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or its salt to PC in the range of 40:60 to 60:40.

[0052] 3. The nutritional composition for use according to any one of Examples 1–2, wherein the nutritional composition further comprises one or more components selected from vitamins A, C and E, phospholipids, selenium, magnesium and other B vitamins.

[0053] 4. The nutritional composition for use according to any of the foregoing embodiments, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia.

[0054] 5. The nutritional composition for use according to any of the foregoing embodiments, wherein the treatment of neurodegenerative diseases involves, i.e., treating and / or preventing and / or delaying symptoms associated with the neurodegenerative disease in a subject suffering from the neurodegenerative disease, or wherein the subject has been diagnosed with a prodromal phase of the neurodegenerative disease, preferably wherein these symptoms involve, i.e., including one or more of the following: - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform daily activities; and / or - Motor symptoms associated with tremor, rigidity, bradykinesia, coordination, and balance; and / or - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional blunting, 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 body temperature regulation.

[0055] 6. The nutritional composition for use according to Example 1, wherein the neurotrauma is selected from traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury.

[0056] 7. The nutritional composition for use according to Example 6, wherein the nerve injury is caused by one or more external factors selected from: - Occupational hazards, including automotive, sports, and workplace accidents; - Explosion and blast damage; -electric shock; - Blunt force trauma; - Penetrating injury, involving an external object, including a bullet or sharp object, that penetrates into the brain, spinal cord, or peripheral nerves.

[0057] 8. The nutritional composition for use according to any one of Examples 1 to 7, wherein the treatment of neurodegenerative diseases involves, i.e., includes, an increase in the outward growth of neurites in a subject with said neurodegenerative disease who is treated with the composition compared to a subject with said neurodegenerative disease who is not treated with the composition, and / or wherein the treatment of neurotrauma involves, i.e., includes, an increase in the length of outward growth of neurons in a subject with said neurotrauma who is treated with the composition compared to a subject with said neurotrauma who is not treated with the composition, preferably wherein the treatment of neurotrauma, brain injury, and / or brain damage includes, compared to a subject with said neurotrauma, brain injury, and / or brain damage who is treated with the composition, an increase in the length of outward growth of neurons in a subject with said neurotrauma, brain injury, and / or brain damage who is treated with the composition.

[0058] 9. The nutritional composition for use according to any of the foregoing 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 neurological trauma, preferably after diagnosis of the neurodegenerative disease and / or after diagnosis or occurrence of the neurological trauma, brain injury and / or brain damage.

[0059] 10. The nutritional composition for use according to any of the foregoing embodiments, wherein the composition comprises the following daily dose: i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg of DHA daily; ii) Vitamin B2 in the range of 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg; iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; and one or more of the following: iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or (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.

[0060] 11. The nutritional composition for use according to any of the foregoing embodiments, wherein the nutritional composition is a liquid nutritional composition, preferably wherein the nutritional composition is an oral nutritional supplement or tube feed.

[0061] 12. A liquid nutrient composition comprising the following: i) DHA; ii) Vitamin B2; iii) Vitamin D3; And from one or more of the following: iv) choline or its salts and / or phosphatidylcholine; and v) Dietary fiber and / or dietary butyrate.

[0062] 13. The liquid nutrient composition according to Example 12, wherein the composition comprises per 100 kcal: i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; ii) 0.4 to 0.6 mg of vitamin B2; iii) 1.3 to 4.5 μg of vitamin D3; And further includes iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline or its salts and / or phosphatidylcholine; and / or (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of 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 of dietary butyrate.

[0063] 14. The liquid nutrient composition according to Example 12 or 13, wherein the composition further 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 Implementation

[0064] This invention relates to a composition comprising i) a combination of omega-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, and further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. Preferably, the composition further comprises one or more selected from vitamins 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) omega-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.

[0065] The present invention further relates to a method for treating neurodegenerative diseases and / or neurotrauma, the method comprising administering to a subject a composition comprising i) a combination of omega-3 fatty acid DHA, ii) vitamin B2 and iii) vitamin D3, and further comprising one or more of the following: iv) choline and / or PC and v) dietary fiber and / or dietary butyrate. The present invention further relates to a method for treating brain injury and / or brain damage, the method comprising administering to a subject a composition comprising i) a combination of omega-3 fatty acid DHA, ii) vitamin B2 and iii) vitamin D3, and further comprising one or more of the following: iv) choline and / or PC and v) dietary fiber and / or dietary butyrate.

[0066] In a preferred embodiment, dietary butyrate is selected from butyrate and butyrate in the form of salts and glycerides (the glycerides comprising one, two, or three butyrate chains). In a preferred embodiment, dietary fiber is selected from pectin, mucilage, gums, GOS, oligofructans, inulin, polyfructose, FOS, arabinogalactan, (hemi)cellulose, resistant starch, soybean fiber, oligosaccharides, and mixtures thereof. Preferably, the dietary fiber comprises or consists of scGOS, lcFOS, and low-viscosity pectin.

[0067] Described alternatively, the invention also relates to the use of compositions for manufacturing neurodegenerative diseases and / or neurotrauma for treating subjects, preferably for treating neurodegenerative diseases selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia, and for treating neurotrauma selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury, the compositions comprising i) a combination of ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. The present invention also relates to the use of compositions for manufacturing compositions for treating brain injury and / or brain damage (selected from those for improving neurological recovery after brain injury and / or brain damage, preventing and / or reducing the worsening of neurological damage caused by brain injury and / or brain damage), the compositions comprising i) a combination of omega-3 fatty acid DHA, ii) vitamin B2, and iii) vitamin D3, further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. Preferably, the compositions according to the invention further comprise one or more selected from vitamins A, B, C and E, phospholipids, selenium, magnesium, and coenzyme Q10.

[0068] Furthermore, the present invention relates to a composition for use in the treatment of neurodegenerative diseases and / or neurotrauma, wherein the neurodegenerative disease is preferably selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and Lewy body dementia, and wherein the neurotrauma is selected from traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury, the composition comprising i) a combination of ω-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. Furthermore, the present invention relates to a composition for use in the treatment of brain injury and / or brain damage, wherein the treatment of brain injury and / or brain damage is selected from improving neurological recovery after brain injury and / or brain damage, preventing and / or reducing the deterioration of neurological damage caused by brain injury and / or brain damage, said composition comprising i) a combination of omega-3 fatty acid DHA, ii) vitamin B2, iii) vitamin D3, and further comprising iv) choline and / or PC and / or v) dietary fiber and / or dietary butyrate. Preferably, the composition according to the invention further comprises one or more selected from vitamins A, B, C and E, phospholipids, selenium, magnesium and coenzyme Q10. In a particular preferred embodiment, the composition comprises a combination of i) omega-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.

[0069] This invention further relates to the treatment of neurodegenerative diseases, and more particularly to the treatment, reduction, delay, or prevention of 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 the neurodegenerative disease involves or includes treating, reducing, delaying, and / or preventing symptoms associated with the neurodegenerative disease in a subject suffering from or in the prodromal stage of the neurodegenerative disease, wherein these symptoms involve one or more of the following: - Cognitive decline associated with memory loss, reduced attention span, and decreased executive function in daily living activities; - Motor symptoms associated with tremor, rigidity, bradykinesia, coordination, and balance; - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional blunting, social withdrawal, and mood swings; - Sensory disturbances associated with loss of sensation, numbness, tingling, or altered perception of touch, pain, or temperature; - Sleep disorders associated with insomnia, excessive daytime sleepiness, sleep fragmentation, restless legs syndrome, and rapid eye movement (REM) sleep behavior disorder; - Autonomic dysfunction associated with orthostatic hypotension, urinary problems, incontinence, constipation, sweating, and changes in body temperature regulation.

[0070] Treatment of neurodegenerative diseases, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia, involves, but includes, improvement in the outward growth of neurites, wherein the improvement in the outward growth of neurites includes an increase in the number and length of neurites per cell in subjects treated with the composition according to the invention compared with subjects not treated with the composition according to the invention.

[0071] 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, i.e., post-diagnosis neuroprotection. Therefore, the treatment of neurodegenerative diseases involves, i.e., neuronal repair or regeneration and neuronal network recovery within the neurodegenerative disease. In embodiments, the treatment of neurodegenerative diseases includes neuronal repair and / or neuronal network recovery. In embodiments, the treatment involves, i.e., symptom treatment and / or delaying the progression of the neurodegenerative disease. Furthermore, the invention further relates to the treatment of neurological trauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury. In some additional embodiments, the invention relates to the treatment of neurological trauma caused by one or more external factors selected from: - Occupational hazards, including automotive, sports, and workplace accidents; - Explosion and blast damage; -electric shock; - Blunt force trauma; - Penetrating injury, involving an external object, including a bullet or sharp object, that penetrates into the brain, spinal cord, or peripheral nerves.

[0072] Treatment of neurological trauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury, involves, specifically, improvements in neurite outgrowth, which refers to an increase in the number and length of neurites per cell in subjects treated with the composition according to the invention compared to subjects not treated with the composition according to the invention. In some embodiments, treatment of neurological trauma, preferably traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury, further involves, specifically, post-diagnosis neuroprotection. Therefore, treatment of neurological trauma involves, specifically, neuronal repair or regeneration and neuronal network recovery following the occurrence of neurological trauma. In embodiments, treatment of neurological trauma includes neuronal repair and / or neuronal network recovery. In embodiments, treatment of neurological trauma includes treating the consequences of neurological trauma and / or preventing the progression of neuronal damage as a consequence of neurological trauma.

[0073] Furthermore, the present invention relates to the treatment of brain injury and / or brain damage, preferably selected from improving neurological recovery following brain injury and / or brain damage, and preventing and / or reducing the deterioration of neurological damage caused by brain injury and / or brain damage. As used herein, neurological recovery and neurological damage include improving the neurological function of the brain (selected from motor, behavioral, emotional, cognitive, and sensory functions). In some additional embodiments, the present invention particularly relates to treating brain injury and / or brain damage caused by internal factors selected from: stroke, ischemia, bacterial and / or viral infection, type 1 or type 2 diabetes, acute alcohol poisoning, cancer treatment, and chemotherapy. In a preferred embodiment, the brain injury and / or brain damage is an acute injury, meaning that the injury occurs within a time span of several days, preferably within 21 days, more preferably within 15 days. In another preferred embodiment, the brain injury and / or brain damage is a localized injury located in a specific or particular region of the brain. In a more preferred embodiment, the present invention relates to the treatment of brain injury and / or brain damage, wherein the brain injury and / or brain damage is a localized and acute injury of the brain. The following examples further describe methods or uses according to the present invention or compositions for use according to the present invention.

[0074] Definitions Throughout this application, the following terms and abbreviations may be used. "Nutritional composition" means a substance or preparation that meets at least a portion of the nutritional needs of a subject. Throughout this disclosure, the terms "nutrition," "nutritional formulation," "enteral nutrition," and "nutritional supplement" are used as non-limiting examples of nutritional compositions. Furthermore, "nutritional composition" may refer to enteral formulations, oral formulations, infant formulas, pediatric subject formulations, children's formulas, growing milks, and / or adult formulations in liquid, powder, gel, paste, solid, concentrate, suspension, or ready-to-use form.

[0075] The term "supplement" or "nutritional supplement" refers to a nutritional product that provides an individual with nutrients that the individual may not be able to conveniently obtain in adequate amounts through other means and can be used to supplement the individual's nutrition. It may be in the form of tablets, capsules, lozenges, or liquids. Supplements typically provide selected nutrients and do not represent a significant portion of the subject's overall nutritional needs, nor do they represent more than 0.1%, 1%, 5%, or 10% of the subject's daily energy requirements.

[0076] As used in this article, “neuroprotection” refers to promoting neuronal repair, limiting neuronal oxidative stress, limiting cell damage, and / or promoting neuronal network recovery after neurotrauma or during neurodegenerative diseases.

[0077] "Prevention" includes reducing the risk and / or severity of neuronal damage in neurodegenerative diseases. The terms "treatment" and "remission" include both: preventative treatment or preventive therapy (preventing a targeted pathological condition or disorder and / or slowing its development) and curative, therapeutic, or disease-modifying treatments, including measures to cure, slow, alleviate, reduce symptoms of a diagnosed pathological condition or disorder, and / or stop its progression; and treatment of patients at risk of developing the disease or suspected of having the disease, and patients who have or have been diagnosed with the disease or medical condition. This term does not necessarily mean treating a subject until full recovery. The terms "treatment" and "remission" also refer to maintaining and / or promoting health in individuals who do not have the disease but may be prone to developing unhealthy conditions. The terms "treatment" and "remission" are also intended to include intensifying or otherwise enhancing one or more major preventative or therapeutic measures. The terms "treatment" and "remission" are further intended to include dietary management of the disease or condition in subjects in need, or dietary management for the prevention or avoidance of the disease or condition.

[0078] As used herein, subjects are mammal subjects, preferably human subjects, more preferably human subjects older than 40 years of age, more preferably human subjects older than 55 years of age, and more preferably human subjects older than 65 years of age.

[0079] As used herein, a “therapeutic effective amount” is an amount that alleviates symptoms, manages the progression of consequences of neurodegenerative diseases and / or neurotrauma, brain injury and / or brain damage, or provides nutritional, physiological or medical benefits to an individual. In preferred embodiments, as used herein, a therapeutic effective amount means an amount that is at least 1, preferably 1.1, even more preferably 1.5, and most preferably 1.7 times the recommended daily intake. The recommended daily intake is defined by agencies such as EFSA or FDA.

[0080] The term "neuron" refers to the outward growth of neurons. As used herein, the term neuron encompasses all such cellular processes of neuronal outward growth (including both axons and dendrites).

[0081] The term “neuron outward growth” refers to the cellular process of neurite growth outward from neurons, or to cells that contain neurites growing outward from neurons, and in this context refers to the number and length of neurites per cell.

[0082] The terms "butyric acid" and "butyrate" (also referring to BA) are used interchangeably and refer to a short-chain fatty acid (SCFA) or its anion that has a four-carbon chain and can covalently bond with another compound, for example, via an ester bond.

[0083] In this document and its claims, the verb “comprising” and its inflections are used in their non-limiting sense to mean including the portion following the word, but not excluding portions not specifically mentioned. Furthermore, when used herein, the term weight percentage (wt%) is a weight percentage based on the total weight. Additionally, unless the context explicitly requires the presence of one / a and only one / a type of element, referring to an element by the indefinite article “a / a” (“a” or “an”) does not preclude the possibility of more than one / a type of element. Therefore, the indefinite article “a / a” (“a” or “an”) generally means “at least one / a type”.

[0084] Composition The method or use according to the invention, or the composition used according to the invention, involves 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 of the invention is a liquid. In one embodiment, preferably, the nutritional composition of the invention is a liquid-as-feed composition. Preferably, the composition is administered orally or as a tube feed.

[0085] In one aspect, the compositions according to the invention can be used as pharmaceutical products comprising one or more pharmaceutically acceptable carrier materials. Such products may contain a daily dose as defined below in one or more dosage units. The dosage units may be in liquid or solid form, wherein in the latter case, the daily dose may be provided by one or more solid dosage units, for example, in one or more capsules or tablets. The pharmaceutical product (preferably for enteral use) may be a solid or liquid galen formulation. Examples of solid galen formulations are tablets, capsules (e.g., hard-shell or soft-shell gelatin capsules), pills, sachets, powders, granules, etc., containing the active ingredient and a conventional galen carrier. Any conventional carrier material may be used. The carrier material may 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. Additionally, additives such as thickeners, flavoring agents, preservatives, stabilizers, emulsifiers, and buffers may be added according to accepted pharmaceutical formulation practices. While individual active ingredients are properly applied in a single composition, they can also be applied in individual dosage units.

[0086] In a preferred aspect, the composition according to the invention can be used as a nutritional product, for example as a nutritional supplement, as an additive to a normal diet, as a fortifier added to a normal diet, or as a complete nutrient. The nutritional product preferably contains at least one component selected from the group consisting of fats, proteins, and carbohydrates, preferably all components. It should be understood that a nutritional product differs from a pharmaceutical product in the presence of nutrients that provide nutrition to the subject administering the composition, particularly the presence of proteins, fats, digestible carbohydrates, and dietary fiber. It may further contain ingredients such as minerals, vitamins, organic acids, and flavorings. Although the term "nutritional health product" is frequently used in the literature, it refers to a nutritional product having pharmaceutical components or pharmaceutical purposes. Therefore, the nutritional composition according to the invention can also be used in nutritional health products.

[0087] 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 having a calorific 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 having a calorific density of 2.2 to 2.6 kcal / ml. The energy provided by the nutrients is calculated using the following Atwater calculation factor: 9 kcal / g lipid, 4 kcal / g protein or digestible carbohydrate, 2 kcal / g fiber, and 0 kcal of other components in the product.

[0088] The amount of lipid fractions can be determined by applying methods known in the art for measuring fat content in food matrices (where 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 dried milk (Lehner, R., Estoppey, A., (1954) Mitt. Lebensmitteluntersuchung Hyg. [Food Inspection and Sanitation Bulletin] 54:183-185). The amount of individual lipid fractions can be determined by applying methods specifically designed for measuring particular fractions or by fractionation of the fat fraction separated from the chloroform-ethanol fraction, as given in method 983.23.

[0089] Suitable sources of omega-3 fatty acids for use in the composition include, but are not limited to, fish oil, krill oil, and algae oil, with fish oil being preferred. Other suitable sources of lipids for use in the composition include, but are not limited to, soybean oil, rapeseed oil (such as canola oil, low-erucic acid rapeseed oil, and canola oil), high-oleic sunflower oil, coconut oil, high-oleic safflower oil, and olive oil. Alternative options include lipids obtained from the milk of non-human mammals, preferably cow's milk, goat's milk, sheep's milk, mare's milk, buffalo milk, yak milk, reindeer milk, donkey milk, and camel milk, especially cow's milk and / or goat's milk. Milk lipids are sometimes also called milk fat or cream fat.

[0090] Therefore, the nutritional composition according to the invention preferably comprises a lipid fraction, preferably a lipid fraction known in the art suitable for nutrition. The composition contains 4 to 12 g lipids / 100 ml, preferably 4.5 to 11 g lipids / 100 ml, more preferably 5 to 10 g / 100 ml. Based on calories, the composition according to the invention may preferably contain 3 to 5.5 g lipids / 100 kcal, preferably 3.5 to 5 g / 100 kcal, more preferably 3.8 to 4.5 g lipids / 100 kcal, based on the total energy content of the composition. The lipid fraction includes polyunsaturated fatty acids and optionally monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs).

[0091] The composition according to the invention preferably contains 4 to 17 g of protein per 100 ml of 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 contains 4-17 g of protein portion per 100 ml of composition. In a preferred aspect, the nutritional composition contains 5 to 16 g of protein portion per 100 ml of composition, more preferably 6-15 g. Most preferably, the composition contains 11 to 14.5 g of protein portion per 100 ml of composition. Based on calories, preferably, the composition according to the invention may contain 4 to 7 g of protein portion per 100 kcal, preferably 4.5 to 6.5 g of protein portion per 100 kcal, more preferably 5 to 6 g of protein portion per 100 kcal, based on the total energy content of the composition.

[0092] Suitable protein sources can be based on milk proteins (such as whey, casein, and mixtures thereof) and plant proteins (such as those from soybeans, potatoes, peas, rapeseed, etc.). The nutritional composition preferably further comprises a carbohydrate portion. The composition preferably contains 9 to 25 g carbohydrates / 100 ml, more preferably 10 to 24 g / 100 ml, and even more preferably 11 to 23 g / 100 ml. Based on calories, the composition according to the invention preferably contains 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. The composition according to the invention preferably contains 4 to 7 g protein / 100 kcal, 3 to 5.5 g lipids / 100 kcal, and 8.5 to 10.5 g carbohydrates / 100 kcal.

[0093] Suitable carbohydrate sources include lactose, glucose, sucrose, fructose, galactose, maltose, starch, isomaltose, and maltodextrin.

[0094] The compositions of the present invention are typically enteral compositions, i.e., intended for oral administration, such as tube feeding, nutritional drinks, and oral nutritional supplements. It is preferably administered in liquid form. Preferably, the composition contains water in which additional components are dissolved or suspended. Thus, the composition is preferably a liquid or a solid (typically a powder or tablet, preferably a powder) that can be reconstituted from a liquid (preferably water) to obtain a liquid composition. The dosage of the components as defined below can be, for example, a daily dose or a concentration per 100 mL or 100 kcal.

[0095] The compositions according to the invention are used to treat neurodegenerative diseases and / or neurotrauma. Furthermore, the compositions according to the invention are used to treat brain injury and / or brain damage. Neurodegenerative diseases are preferably selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia. Neurotrauma is preferably selected from traumatic brain injury (TBI), spinal cord injury (SCI), and peripheral nerve injury. Treatment involves, and includes, treating the symptoms of neurodegenerative diseases and / or delaying the progression of neurodegenerative diseases, as well as treating the consequences of neurotrauma and / or preventing the progression of neuronal damage as a consequence of neurotrauma. Neurotrauma includes trauma caused by external factors such as occupational hazards; blast and explosion injuries; electric shock; blunt force trauma; and penetration of the brain, spinal cord, or peripheral nerves by external objects. Treatment involves, and includes, improving the outward growth of neurites. Treatment of brain injury and / or brain damage preferably improves neurological recovery following brain injury and / or brain damage, and prevents and / or reduces the deterioration of neurological damage caused by brain injury and / or brain damage. Treatment specifically includes addressing the consequences of brain injury and / or brain damage and / or preventing the progression of neuronal damage as a consequence of brain injury and / or brain damage. Brain injury and / or brain damage includes damage or impairment caused by internal factors selected from: stroke, ischemia, bacterial and / or viral infection, type 1 or type 2 diabetes, acute alcohol poisoning, cancer treatment, and chemotherapy. Treatment includes improvements in neurite outgrowth and / or improvements in one or more neurological functions selected from motor, cognitive, behavioral, emotional, and sensory functions.

[0096] The compositions described above can be used as nutritional therapy, nutritional support, medical food, food or nutritional supplement for specific medical purposes. Application of the compositions according to the invention typically occurs after a diagnosis of a neurodegenerative disease and / or during recovery and / or rehabilitation following a neurological injury, and can continue as long as its negative effects are prolonged. Furthermore, application of the compositions according to the invention typically occurs during recovery and / or rehabilitation following a brain injury and / or brain damage, and can continue as long as its negative effects are prolonged. Although positive effects may be observed during the first week of application, application is preferably continued for at least 2 weeks, preferably at least 4 weeks, preferably at least 2 months, more preferably at least 4 months, and even more preferably at least 6 months. Application is preferably initiated on the first day after a diagnosis of a neurodegenerative disease and / or after a neurological injury / diagnosis. Furthermore, it is preferred to initiate application on the first day after a brain injury and / or brain damage / diagnosis.

[0097] The compositions according to the invention can be taken as a liquid composition, preferably an oral nutritional supplement, in one, two, or three doses (typically 125 mL per dose) of 50–250 mL / day during recovery and / or rehabilitation after a diagnosis of neurodegenerative disease and / or after a neurological injury. Furthermore, the compositions according to the invention can be taken as a liquid composition, preferably an oral nutritional supplement, in one, two, or three doses (typically 125 mL per dose) of 50–250 mL / day during recovery and / or rehabilitation after a brain injury and / or brain damage. Preferred daily doses are in the range of 100 to 500 mL, more preferably 125 to 375 mL, and most preferably 200 to 300 mL. Preferably, the compositions are administered enterally. Administration is preferably at least once daily, although alternative dosage regimens can be determined from these figures. Alternatively, the compositions can be administered via tube feeding and continuously. Preferred daily doses for tube feeding are in the range of 1000 to 3000 kcal / day, preferably 1500 to 2500 kcal / day. It is preferable to administer approximately 1 to 2 liters of tube feed per day.

[0098] The methods or uses according to the invention, or the compositions for use according to the invention, relate to compositions comprising i) a combination of omega-3 fatty acid DHA and ii) vitamin B2 and iii) vitamin D3, and further comprising one or more of the following: iv) choline and / or PC; and v) dietary fiber and / or dietary butyrate. In embodiments, the composition further comprises one or more selected from vitamins A, B, C and E, phospholipids, selenium, magnesium, and coenzyme Q10. In another preferred aspect, the compositions according to the invention comprise a combination of i) omega-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.

[0099] Omega-3 fatty acids The compositions of the present invention according to the invention comprise ω-3 polyunsaturated fatty acids (PUFAs), wherein these PUFAs are n-3 LC-PUFAs (long-chain PUFAs). In embodiments, 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-PUFAs; having a chain length of 18 or 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 to DPA (ω-3), thereby increasing the subsequent conversion of DPA to DHA in the brain. In alternative embodiments, the composition comprises only DHA as an ω-3 fatty acid and preferably does not contain EPA.

[0100] In some embodiments, the composition comprises ω-3 fatty acid DHA, vitamin B2, and vitamin D3, and optionally further comprises EPA as an ω-3 fatty acid. In other embodiments, the composition according to the invention may comprise a combination of DHA, vitamin B2, vitamin D3, and EPA, and further comprise one or more of the following: choline and / or PC; and dietary fiber and / or dietary butyrate. In other embodiments, the composition according to the invention may comprise a combination of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more of dietary fiber and dietary butyrate.

[0101] DHA, EPA, and / or DPA can be provided in any form, such as, but not limited to, triglycerides, diglycerides, monoglycerides, free fatty acids, or their salts or esters, phospholipids, lysophospholipids, glyceryl ethers, lipoproteins, ceramides, glycolipids, or combinations thereof. Preferably, the compositions of the present invention comprise at least DHA in the form of triglycerides. Suitable sources of ω-3 LCPUFA and / or DHA and EPA include tuna oil, (other) fish oil, DHA-rich alkyl esters, algae oil, egg yolk, krill oil, or phospholipids rich in ω-3 LCPUFA, such as phosphatidylserine-DHA. Preferably, the composition or the composition intended for use according to the present invention comprises fish oil providing one or more ω-3 LCPUFAs.

[0102] Preferably, DHA is administered at an amount of 100 to 1250 mg / day, more preferably 150 to 1200 mg / day, even more preferably 200 to 1100 mg / day, and most preferably 250 to 1000 mg / day. In embodiments, when the composition is in tube feeding form, the daily dosage of DHA is preferably 200 to 1100 mg / day, more preferably 250 to 1050 mg / day, and most preferably 300 to 1000 mg / day. The composition of the present invention preferably contains 480–680 mg, more preferably 510–650 mg, and most preferably 550–610 mg of DHA per 100 g dry weight of the composition.

[0103] In the embodiments, when the composition is in the form of an oral nutritional supplement, the daily dosage of DHA is preferably 150 to 850 mg / day, more preferably 200 to 800 mg / day, and most preferably 250 to 750 mg / day.

[0104] The compositions of the present invention preferably contain 30 to 240 mg DHA / 100 ml, more preferably 35 to 220 mg DHA / 100 ml, and more preferably 40 to 200 mg DHA / 100 ml. Based on calories, the nutritional compositions according to the present invention preferably contain 20 to 100 mg DHA / 100 kcal, more preferably 25 to 90 mg DHA / 100 kcal, and more preferably 30 to 80 mg DHA / 100 kcal, based on the total energy content of the nutritional composition. These figures are based on the molar weight of DHA.

[0105] Preferably, EPA is administered at an amount of 40 to 350 mg, more preferably 50 to 300 mg, and most preferably 60 to 250 mg EPA / day. In embodiments, when the composition is in tube feeding form, the daily dosage of EPA is preferably 30 to 300 mg / day, more preferably 50 to 280 mg / day, and most preferably 80 to 250 mg / day. The compositions of the present invention preferably contain 100–170 mg, more preferably 110–160 mg, and most preferably 120–150 mg EPA per 100 g dry weight of the composition.

[0106] In the embodiments, when the composition is in the form of an oral nutritional supplement, the daily dosage of EPA is preferably 40 to 220 mg / day, more preferably 50 to 200 mg / day, and most preferably 60 to 180 mg / day.

[0107] The compositions of the present invention preferably contain 5 to 60 mg, more preferably 7 to 55 mg, and most preferably 9 to 50 mg of EPA per 100 ml of composition. Based on calories, the nutritional compositions according to the present invention preferably contain 5 to 30 mg, more preferably 6 to 25 mg, and most preferably 8 to 20 mg of EPA per 100 kcal based on the total energy content of the nutritional composition. These figures are based on the molar weight of EPA. If EPA is present in the composition, the composition preferably contains more DHA than EPA, i.e., the weight ratio of DHA to EPA is preferably greater than 1, more preferably 1.5:1 to 4:1, and even more preferably 2:1 to 4:1.

[0108] Regarding the daily dosage, the use and method of the present invention preferably include administration, which preferably comprises 200 to 2000 mg of ω-3 fatty acids (preferably DHA+EPA+DPA, most preferably DHA+EPA) / day, more preferably 230 to 1750 mg / day, and even more preferably 250 to 1600 mg of EPA / day. The compositions of the present invention preferably comprise 0.3 wt% to 3 wt% of ω-3 fatty acids (more preferably DHA+EPA+DPA, most preferably DHA+EPA) based on total fatty acids, more preferably 0.5 wt% to 2.5 wt% based on total fatty acids, and even more preferably 0.75 wt% to 2.0 wt% of ω-3 fatty acids.

[0109] The compositions of the present invention preferably contain 0.1 wt% to 3.5 wt% DHA based on total fatty acids, more preferably 0.3 wt% to 3 wt% DHA based on total fatty acids, and even more preferably 0.5 wt% to 2.5 wt% DHA based on total fatty acids. The compositions of the present invention preferably contain 0.05 wt% to 0.30 wt% EPA based on total fatty acids, more preferably 0.1 wt% to 0.25 wt% EPA based on total fatty acids, and even more preferably 0.15 wt% to 0.20 wt% EPA.

[0110] The above ratios and amounts take into account and optimize several aspects, including taste (excessive n-3 LC-PUFA levels reduce taste, leading to decreased user compliance) and the balance between DHA and its precursors to ensure optimal efficacy while maintaining a low-volume formulation.

[0111] Vitamin B2 and additional B vitamins The composition of the present invention according to the present invention comprises vitamin B2. In embodiments, the composition may comprise a combination of DHA, vitamin B2, vitamin D3, and EPA, and one or more of the following: choline and / or PC; and dietary fiber and / or dietary butyrate. In other embodiments, the composition may comprise a combination of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more of dietary fiber and dietary butyrate.

[0112] In some embodiments, the composition may comprise additional B vitamins, preferably comprising 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 nicotinamide), 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. B vitamins are known as nutritional cofactors, acting as biochemical "spark plugs" in mitochondria and thus playing a role in further cultivating and supporting optimal neural metabolism. In examples, the composition comprises DHA, vitamin D, and vitamin B2. In other embodiments, the composition comprises DHA, vitamin D, vitamin B2, and optionally vitamin B6 and / or vitamin B9.

[0113] 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 and third B vitamins are selected from the group consisting of vitamins 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; and even more preferably, vitamins B1, B2, B6, B9, and B12. In one embodiment, the composition according to the invention may comprise all of vitamins B1 (thiamine), B2 (riboflavin), B6 ​​(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B9 (folic acid or folic acid), and vitamin B12 (cyanocobalamin). In some embodiments, the composition may comprise additional B vitamins, which, as used herein, are vitamins B1, B3, B5, and B7 in addition to vitamin B2 and one or more of vitamins B6 and B9.

[0114] 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, more preferably 0.8 to 4.9 mg, and even more preferably 0.9 to 4.8 mg. When the composition is in the form of tube feeding, the daily dose 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 dose 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 contains 0.1 to 0.9 mg of vitamin B1 per 100 ml, more preferably 0.15 to 0.8 mg of vitamin B1 per 100 ml, and even more preferably 0.2 to 0.75 mg of vitamin B1 per 100 ml. Based on calories, preferably, the nutritional composition according to the invention may contain 0.05 to 0.4 mg vitamin B1 / 100 kcal, more preferably 0.1 to 0.35 mg vitamin B1 / 100 kcal, and more preferably 0.15 to 0.30 mg vitamin B1 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of thiamine.

[0115] In a preferred embodiment, vitamin B1 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. The RDI is a common reference in the art, for example, referred herein as the Group Reference Intake (PRI), such as the summary of dietary reference values ​​for the EU population obtained by the European Food Safety Authority (EFSA) in September 2017. In the EU, the EFSA-based RDI for vitamin B1 is 0.1 mg / 238.83 calories.

[0116] In the compositions according to the invention, vitamin B2 is preferably present in an amount providing a daily dose ranging from 0.8 to 7.6 mg / day, more preferably from 1 to 7.4 mg / day, more preferably from 1.2 to 7.2 mg / day, and most preferably from 1.4 to 7.2 mg / day. The compositions of the invention preferably contain 1.23–1.53 mg, more preferably 1.27–1.49 mg, and most preferably 1.31–1.44 mg of vitamin B2 per 100 g dry weight of the composition.

[0117] When the composition is in tube feeding form, the daily dosage of vitamin B2 is preferably 2 to 7.6 mg / day, more preferably 2.2 to 7.4 mg / day, and most preferably 2.4 to 7.2 mg / day. When the composition is in the form of an oral nutritional supplement, the daily dosage of vitamin B2 is preferably 0.8 to 4 mg / day, more preferably 1 to 3.8 mg / day, even more preferably 1.2 to 3.6 mg / day, and most preferably 1.4 to 3.6 mg / day. The composition preferably contains 0.1-1.4 mg of vitamin B2 / 100 ml, more preferably 0.2-1.2 mg of vitamin B2 / 100 ml, and more preferably 0.3-1 mg of vitamin B2 / 100 ml. Based on calories, the nutritional composition according to the invention may preferably contain 0.4 to 0.6 mg of vitamin B2 / 100 kcal, preferably 0.15 to 0.5 mg of vitamin B2 / 100 kcal, and more preferably 0.2 to 0.4 mg of vitamin B2 / 100 kcal, based on the total energy content of the composition. The figures above are based on the molar weight of riboflavin.

[0118] In another preferred embodiment, vitamin B2 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. The RDI is a common reference in the art, for example, referred herein as the Group Reference Intake (PRI), such as the summary of dietary reference values ​​for the EU population obtained by EFSA in September 2017. In the EU, the ESFA-based RDI for vitamin B2 is 1.6 mg / day.

[0119] If present in the composition, vitamin B3 is preferably present in an amount providing a daily dose of niacin equivalent in the range of 3 to 45 mg, more preferably 3.5 to 42 mg, and more preferably 3.8 to 40 mg. When the composition is in tube feeding form, the daily dose of vitamin B3 is preferably 11 to 42 mg / day, more preferably 12 to 40 mg / day, and most preferably 12.5 to 39 mg niacin equivalent / day. When the composition is in the form of an oral nutritional supplement, the daily dose of vitamin B3 is preferably 3.4 to 20 mg / day, more preferably 3.6 to 19 mg / day, and most preferably 3.8 to 18 mg niacin equivalent / day. If present, the composition preferably contains 1.2 to 6 mg niacin equivalent / 100 ml, more preferably 1.4 to 5.5 mg niacin equivalent / 100 ml, and more preferably 1.6 to 5 mg niacin equivalent / 100 ml. Based on calories, preferably, the nutritional composition according to the invention may contain 1 to 2.5 mg niacin equivalents / 100 kcal, more preferably 1.1 to 2.2 mg niacin equivalents / 100 kcal, and more preferably 1.2 to 2 mg niacin equivalents / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of niacin.

[0120] 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, more preferably 1 to 14 mg, and more preferably 1.2 to 13 mg. When the composition is in the form of tube feeding, the daily dose 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 dose 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 contains 0.3 to 2.2 mg of vitamin B5 per 100 ml, more preferably 0.4 to 2 mg of vitamin B5 per 100 ml, and more preferably 0.5 to 1.8 mg of vitamin B5 per 100 ml. Based on calories, preferably, the nutritional composition according to the invention may contain 0.2 to 1 mg of vitamin B5 / 100 kcal, more preferably 0.3 to 0.9 mg of vitamin B5 / 100 kcal, and more preferably 0.4 to 0.8 mg of vitamin B5 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of pantothenic acid.

[0121] The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), acts as a coenzyme in multienzymatic reactions of amino acid, glucose, and lipid metabolism, and is known to be a rate-limiting factor in the synthesis of some neurotransmitters.

[0122] 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, more preferably 0.8 to 8 mg, and more preferably 0.9 to 7.5 mg. When the composition is in the form of tube feeding, the daily dose 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 dose 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 contains 0.2 to 1 mg of vitamin B6 per 100 ml, more preferably 0.25-0.8 mg of vitamin B6 per 100 ml, and more preferably 0.3 to 0.7 mg of vitamin B6 per 100 ml. Based on calories, preferably, the composition according to the invention may contain 0.1 to 0.5 mg of vitamin B6 / 100 kcal, more preferably 0.2 to 0.4 mg of vitamin B6 / 100 kcal, and more preferably 0.25 to 0.3 mg of vitamin B6 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of pyridoxine.

[0123] In a preferred embodiment, vitamin B6 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, and more preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, and more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin B6 is 1.65 mg / day.

[0124] 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, more preferably 9 to 90 μg, and even more preferably 9.5 to 85 μg. When the composition is in the form of tube feeding, the daily dose 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 dose 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 even 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, more preferably 2 to 5.5 μg vitamin B7 / 100 kcal, and more preferably 2.5 to 5 μg vitamin B7 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of biotin.

[0125] Vitamin B9, or folic acid, is an essential nutrient that the body converts into folate, which is required for DNA and RNA biosynthesis, DNA repair, and single-carbon metabolic reactions. Decreased folate levels are frequently reported in patients with neurodegenerative diseases (Kronenberg, G, Curr Mol Med [Contemporary Molecular Medicine], 2009).

[0126] 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, more preferably 175 to 800 μg, and more preferably 200 to 750 μg. When the composition is in the form of tube feeding, the daily dose 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 dose 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, more preferably 18 to 75 μg vitamin B9 / 100 kcal, and more preferably 20 to 70 μg vitamin B9 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of folic acid.

[0127] In a preferred embodiment, vitamin B9 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin B9 is 330 µg dietary folate equivalents / day.

[0128] 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, more preferably 2.5 to 19 μg, and more preferably 3 to 18 μg. When the composition is in the form of tube feeding, the daily dose 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 dose 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 caloric content, preferably, the composition according to the invention may contain 0.4 to 1.4 μg vitamin B12 / 100 kcal, more preferably 0.5 to 1.2 μg vitamin B12 / 100 kcal, and more preferably 0.6 to 1 μg vitamin B12 / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of cyanocobalamin.

[0129] In a preferred embodiment, vitamin B12 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, and more preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, and more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin B12 is 4 µg / day.

[0130] Vitamin D3 The compositions of the present invention contain vitamin D3. In embodiments, the compositions may contain a combination of DHA, vitamin B2, vitamin D3, and EPA, as well as one or more of choline and / or PC; and dietary fiber and / or dietary butyrate. In other embodiments, the compositions according to the present invention may contain a combination of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more of dietary fiber and dietary butyrate.

[0131] Vitamin D is a group of fat-soluble open-ring steroids, the two main physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). These are collectively referred to as calciferol. Vitamin D without a subscript refers to all forms of vitamin D, D1, D2, D3, or D4, particularly 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 compositions according to the invention contain vitamin D3.

[0132] 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 calcitriol. Once prepared, the product is stored in hepatocytes until needed and can be released into the plasma, where it binds to α-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: active vitamin D (1,25(OH)2D) and 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, in which C1 is hydroxylated to form 1,25-dihydroxycholecalciferol (1,25(OH)2D, also known as calcitriol). When 1α-hydroxylase is inactive, the enzyme alone hydroxylates the C24 atom to form 24R,25(OH)2D3, which inactivates the molecule and renders it devoid of any biological activity.

[0133] The compositions of the present invention preferably contain 1.5 to 10 μg of vitamin D3 per 100 ml, more preferably 2 to 9 μg of vitamin D3, and even more preferably 2.5 to 8 μg of vitamin D3 per 100 ml of composition. In the most preferred embodiment, the compositions of the present invention contain 10–15 µg of vitamin D3 per 100 ml of composition. According to one embodiment, vitamin D3 is provided in an amount of 5 to 80 μg / day, preferably 6 to 75 μg / day, more preferably 8 to 70 μg / day, and even more preferably 10 to 65 μg / day. The compositions of the present invention preferably contain 38–54 µg, more preferably 40–52 µg, and most preferably 42–50 µg of vitamin D3 per 100 g dry weight of composition.

[0134] In the embodiments, the composition is in the form of tube feeding, and vitamin D3 is preferably provided at an amount of 14 to 80 μg / day, more preferably 16 to 75 μg / day, even more preferably 18 to 70 μg / day, and most preferably 20 to 65 μg / day. In another embodiment, when the composition is in the form of an oral nutritional supplement, vitamin D3 is preferably provided at an amount of 5 to 45 μg / day, more preferably 6 to 40 μg / day, even more preferably 8 to 35 μg / day, and most preferably 10 to 30 μg / day.

[0135] Based on calories, preferably, the nutritional composition according to the invention contains 1.3 to 4.5 μg vitamin D3 / 100 kcal, more preferably 1.5 to 4 μg vitamin D3 / 100 kcal, and 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.

[0136] In another preferred embodiment, vitamin D3 is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 7 times the Recommended Daily Intake (RDI). In a preferred aspect, it is provided at 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the Recommended Daily Intake. The RDI is a common reference in the art, for example, referred herein as the Group Reference Intake (PRI), such as the summary of dietary reference values ​​for the EU population obtained by EFSA in September 2017. In this embodiment, the RDI for vitamin D3 is 15 µg / day.

[0137] Choline The compositions of the present invention preferably further comprise choline. Choline may be present as is or in the form of choline salts and / or choline esters. Choline salts are preferably selected from choline chloride, choline tartrate, choline butyrate, or choline stearate. Choline esters are preferably selected from phosphatidylcholine and lysophosphatidylcholine, preferably phosphatidylcholine. In a preferred embodiment, the compositions of the present invention comprise both of: a) choline or choline salts as is, and b) choline esters, preferably phosphatidylcholine.

[0138] The compositions and methods of the present invention used in practice preferably comprise administration of more than 70 mg of a) choline or choline salts per day, preferably 70 to 1300 mg per day, more preferably 80 to 1200 mg per day, and most preferably 100 to 1100 mg per day. In embodiments, when the composition is in the form of tube feeding, the daily administration of choline or choline salts is preferably 200 to 1400 mg per day, more preferably 300 to 1200 mg per day, and most preferably 350 to 1100 mg per day. In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily administration of choline or choline salts is preferably 70 to 500 mg per day, more preferably 80 to 400 mg per day, and most preferably 100 to 300 mg per day.

[0139] The compositions of the present invention preferably comprise 30 to 180 mg choline or choline salts per 100 ml of liquid composition, more preferably 35 mg to 170 mg choline per 100 ml, more preferably 40 to 160 mg choline per 100 ml, and most preferably 45 mg to 150 mg choline per 100 ml. Based on calories, the nutritional compositions according to the present invention preferably comprise 25 to 110 mg choline per 100 kcal, more preferably 30 to 105 mg choline per 100 kcal, and more preferably 33 to 100 mg per 100 kcal, based on the total energy content of the nutritional composition.

[0140] The figures above are based on choline; the amount of choline salts or esters can be calculated taking into account the molar equivalents of choline. In a preferred embodiment, the composition of the present invention contains, based on 100 g dry weight of the composition, 5–15 mg, more preferably 6–12 mg, and most preferably 7–10 mg of choline (provided in the form of phosphatidylcholine). Throughout this document and the specification, it is intended that the weight of choline provided in the form of choline esters, preferably phosphatidylcholine, is the weight of choline present in the choline esters, preferably phosphatidylcholine.

[0141] Choline is essential for the synthesis of acetylcholine, which is crucial for communication between neurons in the brain and plays a role in cognitive processes such as attention, focus, and memory formation. Choline is a component of phospholipids, which are building blocks of cell membranes, and adequate choline intake ensures the integrity and fluidity of neuronal membranes, which is necessary for neurons to function properly. Choline deficiency can lead to impaired membrane function and affect neuronal signal transduction.

[0142] Furthermore, choline participates in the release of neurotransmitters in neurons. It helps regulate the release of neurotransmitters, including acetylcholine, by maintaining the homeostasis of acetylcholine within synaptic vesicles. Appropriate neurotransmitter release is crucial for neuronal communication and overall brain function. In addition, choline participates in neurogenesis, the process of generating 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 proposed that choline supplementation can improve memory and attention in certain groups, particularly older adults (Liu, L, Behaviourial Neurology, 2021).

[0143] The compositions of the present invention may contain choline in the form of choline esters, preferably provided in the form of phospholipids. Preferably, one or more phospholipids are present in the compositions according to the invention. These one or more phospholipids are selected from the group consisting of phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI), preferably at least phosphatidylcholine. In a preferred embodiment, the phospholipid is a source of choline ester phosphatidylcholine.

[0144] Suitable sources of phospholipids in this article are soybean 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., and Lacprodan® MFGM whey protein concentrate from Arla Foods. Depending on the source, the phospholipids contain approximately 10 wt% to 40 wt% phosphatidylcholine.

[0145] If present, the composition and its use or method of application preferably include an application of 0.6 to 6.6 g / day, preferably 0.8 to 6.4 g / day, more preferably 0.9 to 6.2 g / day, and most preferably 1 to 6 g / day of phospholipids. In one aspect, the amount of phospholipids is about 200 mg / day, preferably 0 to 350 mg / day, more preferably 75 to 300 mg / day, and even more preferably 90 to 250 mg / day. The compositions of the present invention preferably contain 200–290 mg of phospholipids, more preferably 210–280 mg of phospholipids, and most preferably 220–265 mg of phospholipids based on 100 g dry weight of the composition. The phospholipids preferably provide at least phosphatidylcholine. In preferred embodiments, the preferred range for choline provided in the form of phosphatidylcholine is 1 to 15 mg / day, preferably 2 to 12 mg / day, and more preferably 3 to 10 mg / day.

[0146] If phospholipids are present, the composition of the present invention preferably contains 150 to 900 mg / 100 ml, more preferably 200 to 850 mg / 100 ml, and most preferably 250 to 800 mg / 100 ml of phospholipids. In alternative preferred embodiments, the composition of the present invention preferably contains 20–200 mg of phospholipids per 100 ml of composition, more preferably 40–150 mg of phospholipids, and most preferably 50–100 mg of phospholipids. The phospholipids preferably provide at least phosphatidylcholine. In preferred embodiments, the preferred range for choline provided in the form of phosphatidylcholine is 0.5–8 mg per 100 ml of composition, more preferably 1–7 mg, and most preferably 1.5–5 mg. In embodiments, when the composition is in the form of tube feeding, the daily administration of phospholipids is preferably 1 to 7 g / day, more preferably 1.5 to 6.5 g / day, and most preferably 2 to 6 g / day. In another embodiment, when the composition is in the form of an oral nutritional supplement, the daily dosage of phospholipids is preferably 0.5 to 4 g / day, more preferably 0.75 to 3.5 g / day, and most preferably 1 to 3 g / day.

[0147] Based on calories, preferably, the nutritional composition according to the invention contains 100 to 500 mg phospholipids / 100 kcal, more preferably 150 to 400 mg phospholipids / 100 kcal, and more preferably 200 to 350 mg phospholipids / 100 kcal based on the total energy content of the composition. In alternative preferred embodiments, the composition according to the invention preferably contains 20–200 mg phospholipids per 100 kcal based on the total energy of the composition, more preferably 40–150 mg phospholipids, and most preferably 50–100 mg phospholipids. The phospholipids preferably provide at least phosphatidylcholine. In a preferred embodiment, the preferred range for choline provided in the form of phosphatidylcholine is 0.5–8 mg per 100 kcal, more preferably 1–7 mg, and most preferably 1.5–5 mg, based on the total energy of the composition. In a particular embodiment, the nutritional composition according to the invention comprises a) choline or choline salt and b) phosphatidylcholine (PC). In such embodiments, the weight ratio of phosphatidylcholine to choline is typically greater than 0.1, preferably greater than 0.26, particularly 0.30-6, and 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 document, the amount of choline expressed in grams will be calculated by multiplying the molar contribution of choline from all sources of choline (including PC, when orally digested and assuming 100% bioavailability) by the molecular weight of choline (10⁴ g / mol). In this document, the molecular weight of PC is 810 g / mol. Therefore, for example, including 400 mg of choline chloride (molecular weight 139.6 g / mol), 200 mg of phosphatidylcholine, and 200 mg of phospholipids other than PC, the weight ratio of PC to choline would be 200 / [(104 / 139.6) x 400 + (104 / 810) x 200] = 200 / [298 + 25.7] = 0.62.

[0148] The presence of PC is particularly preferred because it reduces the choline (salt) content while still providing a bioavailable source of choline. Furthermore, dietary choline can be metabolized in the intestine to trimethylamine (TMA), which is then oxidized in the liver to trimethylamine N-oxide (TMAO). Both TMA and TMAO are associated with an increased risk of cardiovascular disease (Zhu et al., Cell 2016; Jaworska et al., Cardiovac. Res 2019), therefore, it is preferable to provide choline in its free (salt) form as phosphatidylcholine.

[0149] Preferably, the composition according to the invention comprises a combination of DHA, vitamin B2, vitamin D3, and choline, optionally including one or more of dietary fiber and / or dietary butyrate. In another preferred embodiment, the composition comprises a combination of ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more of dietary fiber and / or dietary butyrate, wherein choline is provided in the form of phosphatidylcholine 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 based on the total choline in the composition, 40 mol% to 60 mol% of the choline is derived from phosphatidylcholine. Preferably, the composition comprises a combination of the following: ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, and one or more of dietary fiber and dietary butyrate, 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. As referred to herein, the molar ratio of choline to PC is called the mol% of choline to PC derived from choline salts. More preferably, the composition contains two or more of these additional ingredients. The additional ingredients and their corresponding amounts will be discussed later.

[0150] Dietary fiber and dietary butyrate The compositions according to the invention preferably contain dietary fiber. In the context of the invention, dietary fiber used in the composition is defined as dietary fiber or dietary fiber blends that produce butyrate, preferably producing butyrate and propionate in a beneficial ratio.

[0151] 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 another embodiment, the composition according to the 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 butyrate. Herein, low-viscosity pectin refers to partially hydrolyzed pectin. In a preferred embodiment, the low-viscosity pectin has a degree of polymerization (DP) of less than 6000 and / or a molecular weight of less than 150 kDa.

[0152] Dietary fiber that can serve as a substrate for the production of fatty acids preferably produces acetate, butyrate, propionate, and hexanoate, more preferably in a beneficial ratio of propionate and butyrate, which allows for increased butyrate production in the subject.

[0153] As used herein, the expression "beneficial butyrate to propionate ratio" means that the weight of butyrate produced by fermentation of fiber or fiber mixtures is at least equal to or greater than the amount of propionate produced by fermentation. For example, locust bean gum or yeast β-glucan produce more propionate than butyrate during fermentation, and these fibers have a butyrate to propionate ratio of less than 1, thus failing to enhance or increase butyrate production. In contrast, soybean fiber and inulin are exemplary fibers that have a beneficial butyrate to propionate ratio during fermentation.

[0154] In a preferred embodiment, the fermentation of dietary fiber beneficially leads to the production of fatty acids, wherein butyrate and propionate are produced in a weight ratio of at least 1, preferably at least 1.1, of butyrate to propionate. The fermentation characteristics of dietary fiber, and the accompanying butyrate to propionate ratio from single-source fiber or fiber blends, can be assessed using fermentation assays known in the art. An exemplary method for assessing fiber fermentation includes using fiber in a fermentation model, employing a fecal sample pool from healthy adults, and exposing the sample to approximately 10 mg / ml of fiber under anaerobic conditions at 37°C for 24 hours.

[0155] In certain embodiments, fiber blends are preferably used as dietary fiber. Exemplary fiber blends used in the context of this 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-galactooligosaccharides, b) inulin, c) resistant starch, and / or d) soluble soybean polysaccharides. This 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.

[0156] Other exemplary fiber blends comprise a) FOS, b) inulin, c) soybean fiber, d) resistant starch, e) gum arabic, and / or f) cellulose. 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. Other exemplary fiber blends comprise a) arabinoxylan, b) oat β-glucan, c) pectin, and / or d) resistant starch. The fiber blend 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.

[0157] The preferred fiber blend used in this composition comprises a) scGOS, b) lcFOS and c) low-viscosity pectin. The fiber blend is fermentable and, in particular, produces butyric acid at a beneficial C4:C3 weight ratio of at least 1, preferably at least 1.1, and even more preferably at least 1.5.

[0158] ScGOS refers to short-chain GOS with a low degree of polymerization, typically composed of 2 to 6 galactose units. Examples of scGOS include, but are not limited to, galactobiose, lactulose, and isomaltooligosaccharides. In preferred embodiments, scGOS comprises galactooligosaccharides having β-(1,4), β-(1,3), and / or β-(1,6) glycosidic bonds and terminal glucose. Trans-galactooligosaccharides are available, for example, under the trade names Vivinal® GOS (FrieslandCampina Ingredients), Bi2muno (Clasado), Cup-oligo (Nissin Sugar), and Oligomate55 (Yakult).

[0159] LcFOS refers to a long-chain FOS having a high degree of polymerization, preferably greater than 8, more preferably 10 to 100, and most preferably 20 to 50. Examples of lcFOS include, but are not limited to, inulin and oligofructose. LcFOS can refer to an oligosaccharide containing β-linked fructose units, which are preferably linked by β-(2,1) and / or β-(2,6) glycosidic bonds. Preferably, lcFOS contains glucose terminally linked by β-(2,1) glycosidic bonds. In another preferred embodiment, inulin is used. Inulin is an lcFOS type in which at least 75% of the glycosidic bonds are β-(2,1) bonds. Typically, the average chain length of inulin is 8 to 60 monosaccharide units. Suitable lcFOS for use in compositions according to the method or use of the invention are commercially available under the trade name Raftiline® HP (Orafti Corporation). Other suitable sources are Raftilose (Orafti), Fibruloseh and Fibruline (Cosucra), and Frutafit and Frutalose (Sensus).

[0160] 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, and even more preferably in a ratio of about 9 / 1.

[0161] 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 specifically processed to have a lower molecular weight and reduced gel-forming ability compared to conventional pectin. Modifying pectin to produce low-viscosity pectin involves various methods, such as acid hydrolysis or enzymatic treatment. These methods break down the long chains of pectin molecules into shorter chains, resulting in lower viscosity and improved dispersibility in liquid formulations.

[0162] In another preferred embodiment, the composition comprises a mixture of dietary fiber including scGOS, lcFOS and low-viscosity pectin, 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5.

[0163] Preferably, the daily dose contains 2.5 to 12.5 g, more preferably 3 to 12 g, and most preferably 3.5 to 11.5 g of dietary fiber. In another preferred embodiment, the composition contains 0.5 to 4.0 g, more preferably 1.0 to 3.5 g, and most preferably 1.5 to 3.0 g of dietary fiber per 100 ml of composition. In another preferred embodiment, the composition contains 0.75 to 2.5 g, more preferably 1.0 to 2.0 g, and most preferably 1.1 to 1.5 g of dietary fiber per 100 kcal of composition. The compositions of the present invention preferably contain 9.0–11.3 g, more preferably 9.2–11 g, and most preferably 9.8–10.8 g of dietary fiber per 100 g dry weight of the composition.

[0164] The compositions of the present invention according to the present invention preferably contain dietary butyrate. In the context of the present invention, dietary butyrate used in the composition is defined as butyric acid, butyrate, butyrate ester, such as butyrate in the form of a glycerol ester (which contains one, two or three butyric acid chains).

[0165] Dietary butyrate can be provided from any suitable source known in the art. Non-limiting sources of dietary butyrate include animal-derived fats and derivatives, such as, but not limited to, milk, milk fat, butter fat, butter oil, butter, buttermilk, cream whey, and cream; microbial fermentation derivatives, such as, but not limited to, yogurt and fermented buttermilk; and plant-derived seed oil products, such as pineapple and / or pineapple oil, almond and / or almond oil, barley, oats, brown rice, wheat bran, green beans, legumes, leafy green vegetables, apples, kiwifruit, and oranges. In some embodiments, dietary butyrate is synthetically produced, but preferably, dietary butyrate is provided from natural sources as defined above.

[0166] In some embodiments, the composition comprises dietary butyrate in the form of sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, choline butyrate, and combinations thereof. In some embodiments, the dietary butyrate comprises a suitable butyrate that has been coated with one or more fats or lipids. Preferably, the dietary butyrate is provided as a butyrate ester, for example, as part of a (tri)glyceride in a preferred embodiment. This is advantageous because butyrate is volatile (and foul-smelling) when provided in free or salt form. In the (tri)glyceride form, the butyrate is released in and after the stomach due to the action of lipases.

[0167] In a preferred embodiment, the dietary butyrate used in the composition comprises a butyrate-containing glyceride, preferably a butyrate-containing triglyceride. In the context of this invention, a butyrate-containing glyceride comprises at least one butyrate chain, preferably at least two or three butyrate chains. Preferably, the dietary butyrate comprises a tributyrate glyceride (i.e., a triglyceride in which three butyrate chains are attached to the glycerol backbone via ester bonds). If the butyrate is added as a triglyceride or diglyceride, there may be 0, 1, or 2 other side chains that are fatty acid chains other than butyrate; or in other words, the diglyceride or triglyceride may be a mixed glyceride in which at least one fatty acid chain is a butyrate.

[0168] Preferably, based on the weight of butyric acid, the daily dose comprises 0.125 g to 0.65 g of dietary butyrate, more preferably 0.025 g to 0.65 g, and most preferably 0.043 g to 0.65 g of dietary butyrate.

[0169] In another preferred embodiment, the composition comprises, based on the weight of butyric acid, 0.01 to 0.175 g dietary butyrate / 100 ml, more preferably 0.02 to 0.175 g dietary butyrate / 100 ml, and most preferably 0.035 to 0.175 g dietary butyrate / 100 ml. In another preferred embodiment, the composition comprises, based on the weight of butyric acid, 0.015 to 0.25 g dietary butyrate / 100 kcal, more preferably 0.03 to 0.25 g dietary butyrate / 100 kcal, and most preferably 0.05 to 0.25 g dietary butyrate / 100 kcal.

[0170] In another preferred embodiment, the composition according to the invention comprises a mixture of dietary fiber and dietary butyrate. Preferably, the mixture of dietary fiber and dietary butyrate contains at least 50 wt% dietary fiber, more preferably, the weight ratio of dietary fiber to dietary butyrate in the mixture is in the range of 80:20 to 50:50, more preferably 75:25 to 60:40.

[0171] Neurons have high energy requirements, and butyrate, derived from dietary fiber, can serve as an alternative energy source for neurons. It can be metabolized by neurons to produce ATP (adenosine triphosphate), the primary energy transporter for cells. Furthermore, butyrate exhibits 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 crucial role in neuronal growth, survival, and synaptic plasticity, and is essential for learning and memory. Finally, butyrate possesses anti-inflammatory properties that can help regulate inflammatory responses in neurons. Excessive inflammation in the brain can be detrimental to neuronal health, and the anti-inflammatory effects of butyrate can contribute to neuroprotection.

[0172] Vitamin A The compositions of the present invention may further comprise vitamin A. Vitamin A is a fat-soluble vitamin that occurs in several forms, such as retinol, retinal, retinoic acid, or retinyl esters. Any functional form of vitamin A known in the art is applicable herein, including retinol (especially retinyl esters), retinal, retinoic acid, β-carotene, provitamin A, or any combination thereof. Preferably, the composition comprises retinol, particularly retinyl acetate and / or retinyl palmitate.

[0173] Vitamin A intake or requirements are usually expressed in the form of retinol equivalents (REs). One RE is defined as the biological activity associated with 1 µg of all-trans retinol. Therefore, 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.

[0174] If present in the composition, vitamin A is preferably administered at 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, and most preferably 375 to 2600 μg retinol equivalents / day. In preferred embodiments, vitamin A is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). Preferably, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin A is 700 µg retinol equivalents / day. In the examples, the composition is in tube feeding form, and the daily dose of vitamin A is preferably 700 to 2850 μg retinol equivalents / day, more preferably 800 to 2750 μg retinol equivalents / day, and most preferably 850 to 2600 μg retinol equivalents / day.

[0175] In another embodiment, the composition is in the form of an oral nutritional supplement, and the daily dosage of vitamin A is preferably 300 to 1200 μg retinol equivalents / day, more preferably 350 to 1150 μg retinol equivalents / day, and most preferably 375 to 1125 μg retinol equivalents / day. The compositions of the present invention may preferably contain vitamin A, preferably 50 to 400 μg retinol equivalents / 100 ml of composition, more preferably 75 to 350 μg retinol equivalents / 100 ml of composition, and most preferably 100 to 300 μg retinol equivalents / 100 ml of composition.

[0176] Based on calories, preferably, the nutritional composition according to the invention may contain 60 to 150 μg retinol equivalents / 100 kcal, more preferably 70 to 140 μg retinol equivalents / 100 kcal, and more preferably 80 to 130 μg retinol equivalents / 100 kcal, based on the total energy content of the nutritional composition.

[0177] Vitamin C The compositions of the present invention may further comprise vitamin C. Vitamin C is an antioxidant that can provide beneficial characteristics in neurodegenerative diseases and after nerve trauma and brain injury and / or brain damage. Vitamin C includes its functional equivalents (including sodium ascorbate and calcium ascorbate) and may 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 the composition is in the form of a tube feed, the daily dose of vitamin C is preferably 140 to 600 mg / day, more preferably 160 to 575 mg / day, and most preferably 180 to 550 mg / day. When the composition is in the form of an oral nutritional supplement, the daily dose of vitamin C is preferably 80 to 320 mg / day, more preferably 90 to 300 mg / day, and most preferably 95 to 290 mg / day. In one embodiment, if present, vitamin C is present in an amount ranging from 10 to 100 mg per 100 ml of the composition, preferably from 15 to 90 mg, and more preferably from 20 to 80 mg. Based on calories, the composition according to the invention may preferably contain 12 to 40 mg vitamin C / 100 kcal, preferably 14 to 35 mg vitamin C / 100 kcal, and more preferably 16 to 32 mg vitamin C / 100 kcal, based on the total energy content of the composition. These figures are based on the molar weight of ascorbic acid.

[0178] In a preferred embodiment, vitamin C is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, and more preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, and more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin C is 102.5 mg / day.

[0179] Vitamin E The compositions according to the invention may contain vitamin E. Vitamin E refers to compounds known in the art that have vitamin E activity, typically tocopherol and / or its equivalents.

[0180] If included, vitamin E may be present in the composition at a daily dose providing α-TE in the range of 8 to 75 mg, preferably 10 to 70 mg, more preferably 12.5 to 70 mg. When the composition is in tube feeding form, the daily dose 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 dose 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 amounts of vitamin E prevent oxidative damage to the site of injury. In one embodiment, tocopherol and / or its equivalent are present in an amount in the range of 2 to 14 mg α-TE per 100 ml of the composition, preferably 2.5 to 12 mg α-TE, and more preferably 2.75 to 10 mg α-TE. Based on calorie content, preferably, the composition according to the invention may contain 1 to 5.5 mg α-TE / 100 kcal, more preferably 1.5 to 5 mg α-TE / 100 kcal, and more preferably 2 to 4.5 mg α-TE / 100 kcal, based on the total energy content of the composition.

[0181] In preferred embodiments, vitamin E is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based vitamin E is 12 mg / day. As used herein, the term "tocopherol and / or its equivalents" includes tocopherols (e.g., α-tocopherol and γ-tocopherol), tocotrienols, their pharmaceutically and / or nutritionally acceptable derivatives, and any combination thereof. The figures above are based on α-tocopherol equivalents (α-TE) and their molecular weight, as recognized in the art.

[0182] Vitamin K1 The compositions according to the invention may optionally contain vitamin K, preferably vitamin K1, although it is preferred that the composition does not contain or contains only a minimal amount of vitamin K. Vitamin K is a general name for a group of compounds containing a 2-methyl-1,4-naphthoquinone nucleus and having a different lipophilic side chain at position 3, hereinafter also referred to as "K group vitamins". Vitamin K is naturally present in the form of vitamin K1 (phytonaphthoquinone, phytonaphthoquinone, α-phylloquinone) and vitamin K2 (toluidine), vitamin K2 being produced by gastrointestinal bacteria in essentially two different subtypes, namely vitamin K2(35) (C46H64O2) and vitamin K2(30) (C41H56O2). Vitamin K3 (phytonaphthoquinone) is a provitamin that can be converted into vitamin K2 by animals.

[0183] If present in the composition, vitamin K1 is preferably present at a daily dose of up to 240 μg / day, more preferably up to 200 μg / day, and more preferably up to 100 μg / day. The compositions of the present invention preferably contain less than 40 μg vitamin K1 / 100 ml, more preferably less than 35 μg vitamin K1 / 100 ml, and even more preferably less than 30 μg vitamin K1 / 100 ml. Based on calories, preferably, the compositions according to the present invention may contain less than 18 μg vitamin K1 / 100 kcal, more preferably less than 16 μg vitamin K1 / 100 kcal, and more preferably less than 15 μg vitamin K1 / 100 kcal based on the total energy content of the composition. These figures are based on the molar weight of phylloquinone. In a preferred embodiment, the composition contains less than 15 µg vitamin K1 / 100 kcal.

[0184] Selenium The compositions of the present invention may contain selenium. The antioxidant activity of selenium can advantageously prevent and / or inhibit damage to brain regions.

[0185] If present in the composition, selenium is preferably present in an amount providing a daily dose in the range of 30 to 275 μg, more preferably 35 to 250 μg, and even more preferably 38 to 225 μg. When the composition is in the form of tube feeding, the daily dose of selenium is preferably 60 to 275 μg / day, more preferably 70 to 250 μg / day, and most preferably 75 to 225 μg / day. When the composition is in the form of an oral nutritional supplement, the daily dose of selenium is preferably 25 to 140 μg / day, more preferably 30 to 130 μg / day, and most preferably 35 to 120 μg / day. The composition of the present invention preferably contains 8 to 45 μg selenium / 100 ml, more preferably 10 to 40 μg selenium / 100 ml, and even more preferably 11 to 35 μg selenium / 100 ml. Based on heat, preferably, the composition according to the invention may contain 4 to 18 μg selenium / 100 kcal, more preferably 6 to 16 μg selenium / 100 kcal, and more preferably 8 to 14 μg selenium / 100 kcal, based on the total energy content of the composition.

[0186] In a preferred embodiment, selenium is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based selenium is 70 µg / day.

[0187] Magnesium The compositions of this invention may contain magnesium. Magnesium plays a vital role in nerve transmission and neuromuscular conduction. It also provides protection against overexcitation that can lead to neuronal cell death (excitotoxicity).

[0188] If present in the composition, magnesium is preferably present in an amount providing a daily dose in the range of 125 to 850 mg, more preferably 150 to 800 mg, and more preferably 170 to 750 mg. When the composition is in the form of tube feeding, the daily dose of magnesium is preferably 200 to 780 mg / day, more preferably 220 to 760 mg / day, and most preferably 240 to 740 mg / day. When the composition is in the form of an oral nutritional supplement, the daily dose of magnesium is preferably 150 to 600 mg / day, more preferably 160 to 550 mg / day, and most preferably 170 to 525 mg / day. The composition of the present invention preferably contains 20 to 160 mg magnesium / 100 ml, more preferably 25 to 150 mg magnesium / 100 ml, and more preferably 30 to 140 mg magnesium / 100 ml. Based on calorie content, preferably, the composition according to the invention may contain 10 to 70 mg magnesium / 100 kcal, more preferably 15 to 65 mg magnesium / 100 kcal, and more preferably 20 to 60 mg magnesium / 100 kcal, based on the total energy content of the composition.

[0189] In a preferred embodiment, magnesium is preferably present in a therapeutically effective amount if the nutritional supplement or composition provides at least 1.2 times, preferably at least 1.3 times, and preferably no more than 20 times, and more preferably no more than 10 times, the recommended daily intake (RDI). In a preferred aspect, it provides 1.2 to 5 times, preferably 1.3 to 4.5 times, and more preferably 1.4 to 4 times the recommended daily intake. In the EU, the RDI for ESFA-based magnesium is 325 mg / day.

[0190] This composition may contain additional minerals, including but not limited to sodium, potassium, chloride, calcium, phosphorus, iron, zinc, copper, manganese, fluorite, molybdenum, chromium, and iodine. The amounts shall conform to the general recommendations of the FSMP regarding nutritional requirements.

[0191] Coenzyme Q10 The compositions according to the invention preferably contain a therapeutically effective amount of coenzyme Q10. In examples, the compositions according to the invention contain a combination of DHA, vitamins B2 and D3 with coenzyme Q10. In other examples, the compositions according to the invention may contain a combination of the following: ω-3 fatty acids DHA and EPA, vitamin B2, vitamin D3, choline, coenzyme Q10, and one or more of dietary fiber and dietary butyrate.

[0192] Coenzyme Q10 (also known as CoQ10, Q10, vitamin Q10, ubiquinone, and ubiquitin) is a benzoquinone compound synthesized naturally in the human body. The "Q" and "10" in the name refer to the quinone chemical group and the 10 isoprenyl chemical subunits that are part of the compound's structure, respectively. As used herein, coenzyme Q10 refers to ubiquinone (2,3-dimethoxy-5-methyl-6-decanoisoprenylbenzoquinone) and / or its functional analogues, including ubiquinone alcohol.

[0193] Coenzyme Q10 is a fat-soluble natural substance that primarily functions as an essential enzyme cofactor in the mitochondrial electron transport chain. It is also a key factor in oxidative phosphorylation and aerobic cellular respiration via the production of adenosine triphosphate (ATP) (Egil Fosslien; Mitochondrial Medicine - Molecular Pathology of Defective Oxidative Phosphorylation, Annals of Clinical and Laboratory Science, 2000).

[0194] Due to its lipid solubility and its ability to exist in both fully reduced (ubiquinone alcohol) and fully oxidized (ubiquinone) forms, CoQ10 has been shown to function as both an antioxidant and an electron carrier. CoQ10 accepts electrons derived from complex I (NADH ubiquinone oxidoreductase) and complex II (succinate ubiquinone reductase), and then transports them to complex III (ubiquinone alcohol cytochrome c reductase). Natural sources of CoQ10 and / or similar compounds suitable for use in this invention include fungi, yeasts or bacteria, extracts or isolates of canola oil or soybean oil.

[0195] Preferably, the composition comprises 0.0001 mg to 0.8 mg of coenzyme Q10 / day, more preferably 0.001 to 0.6 mg of coenzyme Q10 / day, and even more preferably 0.01 to 0.4 mg of coenzyme Q10 / day. 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, and even more preferably 0.001 to 0.3 mg / 100 ml.

[0196] According to another embodiment, coenzyme Q10 is preferably provided in an amount of 0.0001 to 0.3 mg / 100 kcal, more preferably 0.001 to 0.3 mg / 100 kcal, and even more preferably 0.001 to 0.2 mg / 100 kcal. These figures are based on the molar weight of ubiquinone.

[0197] LA / ALA In addition to one or more ω-3 fatty acids, the lipid portion may also contain lipids as sources 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 mixtures of one or more of the above. Preferably, the compositions of the present invention contain at least one, preferably at least two, lipid sources selected from the group consisting of: soybean oil, rapeseed oil (such as colza oil, low-erucic acid rapeseed 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, more preferably 7:1 to 4:1, and more preferably 6:1 to 5:1.

[0198] If present in the composition, the composition of the present invention preferably contains 0.2 to 3.5 g LA / 100 ml, more preferably 0.3 to 3 g LA / 100 ml, and even more preferably 0.4 to 2.5 g LA / 100 ml. Based on caloric content, the composition according to the present invention may preferably contain 0.1 to 1.5 g LA / 100 kcal, more preferably 0.2 to 1.1 g LA / 100 kcal, and even more preferably 0.25 to 1 g LA / 100 kcal, based on the total energy content of the composition.

[0199] If present in the composition, the composition of the present invention preferably contains 0.02 to 0.2 g ALA / 100 ml, more preferably 0.05 to 0.15 g ALA / 100 ml, and even more preferably 0.06 to 0.1 g ALA / 100 ml. Based on caloric content, the composition according to the present invention may preferably contain 0.03 to 0.08 g ALA / 100 kcal, preferably 0.04 to 0.07 g ALA / 100 kcal, and even more preferably 0.05 to 0.065 g ALA / 100 kcal.

[0200] In the embodiments, each daily dose of the composition according to the invention comprises: (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; and one or more of the following: (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or (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 butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0201] In the embodiments, each daily dose of the composition according to the invention comprises: (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; as well as v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber selected from scGOS, lcFOS and low-viscosity pectin, and / or 0.125 g to 0.65 g of dietary butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0202] In the embodiments, each daily dose of the composition according to the invention comprises: (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 (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; and one or more of the following: (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or (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 butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0203] In the embodiments, each daily dose of the composition according to the invention comprises: (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; as well as (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; wherein the composition preferably contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40, and optionally... (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 butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0204] In the embodiments, each daily dose of the composition according to the invention comprises: (i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg DHA; and (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; With the following combinations: (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and optional v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.125 g to 0.65 g of dietary butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0205] In the embodiments, each daily dose of the composition according to the invention comprises: (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 (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; With the following combinations: (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg 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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; as well as v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.125 g to 0.65 g of dietary butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0206] In the embodiments, each daily dose of the composition according to the invention comprises: (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 (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6; (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9; and one or more of the following: (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or (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 butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0207] In the embodiments, each daily dose of the composition according to the invention comprises: (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 (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6; (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9; as well as (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; as well as v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber selected from scGOS, lcFOS and low-viscosity pectin, and / or 0.125 g to 0.65 g of dietary butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0208] In the embodiments, each daily dose of the composition according to the invention comprises: (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 (ii) Vitamin B2 in doses ranging from 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably from 1.2 to 7.2 mg; and (iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; (vi) 0.7 to 9 mg, preferably 0.8 to 8 mg, more preferably 0.9 to 7.5 mg of vitamin B6; (vii) 150 to 900 μg, preferably 175 to 800 μg, more preferably 200 to 750 μg of vitamin B9; as well as (iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg 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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; as well as v) 2.5 to 12.5 g, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.125 g to 0.65 g of dietary butyrate, preferably 0.025 g to 0.65 g, more preferably 0.043 g to 0.65 g of dietary butyrate.

[0209] 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) for each daily dose implemented as described above further comprises one or more of the following: (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; (ix) 0.7 to 5 mg, preferably 0.8 to 4.9 mg, more preferably 0.9 to 4.8 mg of vitamin B1; (x) 2 to 20 μg, preferably 2.5 to 19 μg, more preferably 3 to 18 μg of vitamin B12; (xi) 75 to 700 mg, preferably 85 to 600 mg, more preferably 95 to 550 mg of vitamin C; (xii) 8 to 75 mg, preferably 10 to 70 mg, more preferably 12.5 to 70 mg of α-TE; (xiii) 30 to 275 μg, preferably 35 to 250 μg, more preferably 38 to 225 μg of selenium; and (xiv) 125 to 850 mg, preferably 150 to 800 mg, more preferably 170 to 750 mg of magnesium (xv) 0.0001 mg to 0.8 mg coenzyme Q10, more preferably 0.001 to 0.6 mg coenzyme Q10, and even more preferably 0.01 to 0.4 mg coenzyme Q10.

[0210] In another preferred embodiment, each daily dose of the composition comprises at least one of (i), (ii), (iii), (iv), and (v), (vi), and (vii), and one or more of the following: (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; (ix) 0.7 to 5 mg, preferably 0.8 to 4.9 mg, more preferably 0.9 to 4.8 mg of vitamin B1; (x) 2 to 20 μg, preferably 2.5 to 19 μg, more preferably 3 to 18 μg of vitamin B12; (xi) 75 to 700 mg, preferably 85 to 600 mg, more preferably 95 to 550 mg of vitamin C; (xii) 8 to 75 mg, preferably 10 to 70 mg, more preferably 12.5 to 70 mg of α-TE; (xiii) 30 to 275 μg, preferably 35 to 250 μg, more preferably 38 to 225 μg of selenium; and (xiv) 125 to 850 mg, preferably 150 to 800 mg, more preferably 170 to 750 mg of magnesium (xv) 0.0001 mg to 0.8 mg coenzyme Q10, more preferably 0.001 to 0.6 mg coenzyme Q10, and even more preferably 0.01 to 0.4 mg coenzyme Q10 In another preferred embodiment, each daily dose of the composition comprises at least one of (i), (ii) and (iii), (vi) and (vii), and optionally (iv) and / or (v), a combination of one or more selected from (vii) – (xv), further comprising at least one of the following: (xvi) 3 to 45 mg, preferably 3.5 to 42 mg, more preferably 3.8 to 40 mg of vitamin B3 (niacin equivalent); (xvii) 0.8 to 15 mg, preferably 1 to 14 mg, more preferably 1.2 to 13 mg of vitamin B5; (xviii) 8 to 95 μg, preferably 9 to 90 μg, more preferably 9.5 to 85 μg of vitamin B7.

[0211] This article also provides a liquid nutrition composition, which contains per 100 ml: (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; and one or more of the following: (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 / or v) 1.5 to 4.5 g, preferably 2 to 4 g, more preferably 2.5 to 3.5 g of dietary fiber, and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0212] This article also provides a liquid nutrition composition, which contains per 100 ml: (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; as well as (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; as well as (v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g of dietary fiber, and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0213] This article also provides a liquid nutrition composition, which contains per 100 ml: (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 (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; and one or more of the following: (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 / or (v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g of dietary fiber, and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0214] This article also provides a liquid nutrition composition, which contains per 100 ml: (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; as well as (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; and optional v) 1.5 to 4.5 g, preferably 2 to 4 g, more preferably 2.5 to 3.5 g of dietary fiber, and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0215] This article also provides a liquid nutrition composition, which contains per 100 ml: (i) 30 to 240 mg, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; and (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; With the following combinations: (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 / or v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0216] This article also provides a liquid nutrition composition, which contains per 100 ml: (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 (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; as well as (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; as well as v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate.

[0217] This article also provides a liquid nutrition composition, which contains per 100 ml: (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 (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 (iii) 1.5 to 10 μg, preferably 2 to 9 μg, more preferably 2.5 to 8 μg of vitamin D3; and one or more of the following: (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; and / or v) 0.5 to 4.0 g, preferably 1.0 to 3.5 g, more preferably 1.5 to 3.0 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.01 to 0.175 g of dietary butyrate, preferably 0.02 to 0.175 g, more preferably 0.035 to 0.175 g of dietary butyrate. and at least one of (vi) and (vii); (vi) 0.2 to 1 mg, preferably 0.25 to 0.8 mg, more preferably 0.3 to 0.7 mg of vitamin B6; (vii) 20 to 225 μg, preferably 25 to 200 μg, more preferably 30 to 175 μg of vitamin B9.

[0218] In another preferred embodiment, the liquid nutrient 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: (viii) 50 to 400 μg, preferably 75 to 350 μg, more preferably 100 to 300 μg of retinol equivalent vitamin A; (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; (x) 0.5 to 3 μg, preferably 0.6 to 2.6 μg, more preferably 0.7 to 2.4 μg of vitamin B12; (xi) 10 to 100 mg, preferably 15 to 90 mg, more preferably 20 to 80 mg of vitamin C; (xii) 2 to 14 mg, preferably 2.5 to 12 mg, more preferably 2.75 to 10 mg of α-TE; (xiii) 8 to 45 μg, preferably 10 to 40 μg, more preferably 11 to 35 μg of selenium; (xiv) 20 to 160 mg, preferably 25 to 150 mg, more preferably 30 to 140 mg of magnesium; and (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.

[0219] In another preferred embodiment, the liquid nutrient composition may further comprise one or more of the following per 100 ml: (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); (xvii) 0.3 to 2.2 mg, preferably 0.4 to 2 mg, more preferably 0.5 to 1.8 mg of vitamin B5; (xviii) 2 to 14 mg, preferably 3 to 12 mg, more preferably 3.5 to 11 mg of vitamin B7.

[0220] This article further provides a liquid nutrition composition containing, per 100 kcal: (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; and one or more of the following: (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 / or (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of dietary fiber, and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0221] This article further provides a liquid nutrition composition containing, per 100 kcal: (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; as well as (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; as well as (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of dietary fiber, and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0222] This article further provides a liquid nutrition composition containing, per 100 kcal: (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 (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; and one or more of the following: (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 / or (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of dietary fiber, and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0223] This article further provides a liquid nutrition composition containing, per 100 kcal: (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; as well as (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; and optional (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of dietary fiber, and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0224] This article further provides a liquid nutrition composition containing, per 100 kcal: (i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; and (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; With the following combinations: (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 / or v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0225] This article further provides a liquid nutrition composition containing, per 100 kcal: (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 (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; With the following combinations: (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; as well as v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0226] This article further provides a liquid nutrition composition containing, per 100 kcal: (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 (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 (iii) 1.3 to 4.5 μg, preferably 1.5 to 4 μg, more preferably 2 to 3.5 μg of vitamin D3; A combination of at least one of (vi) and (vii); (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; (vii) 16 to 80 μg, preferably 18 to 75 μg, more preferably 20 to 70 μg of vitamin B9; and one or more of the following: (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 contains v a Phosphatidylcholine and v b Choline or its salt, wherein at least 20 mol% of the choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or salt to PC in the range of 40:60 to 60:40; and / or v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of 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, and most preferably in the range of 8:1:1.5 to 10:1:2.5; and / or 0.015 to 0.25 g of dietary butyrate, preferably 0.03 to 0.25 g, more preferably 0.05 to 0.25 g of dietary butyrate.

[0227] In another preferred embodiment, the liquid nutrient composition comprises at least one of (i), (ii) and (iii), (vi) and (vii) per 100 kcal, and optionally a combination of (iv) and / or (v), further comprising one or more of the following: (viii) 60 to 150 μg, preferably 70 to 140 μg, more preferably 80 to 130 μg of retinol equivalent vitamin A; (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; (xi) 12 to 40 mg, preferably 14 to 35 mg, more preferably 16 to 32 mg of vitamin C; (xii) 1 to 5.5 mg, preferably 1.5 to 5 mg, more preferably 2 to 4.5 mg of α-TE; (xiii) 4 to 18 μg, preferably 6 to 16 μg, more preferably 8 to 14 μg of selenium; and (xiv) 10 to 70 mg, preferably 15 to 65 mg, more preferably 20 to 60 mg of magnesium (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.

[0228] In another preferred embodiment, the liquid nutrient composition may further comprise one or more of the following per 100 kcal: (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); (xvi) 0.2 to 1 mg, preferably 0.3 to 0.9 mg, more preferably 0.4 to 0.8 mg of vitamin B5; (xvii) 1.5 to 6 mg, preferably 2 to 5.5 mg, more preferably 2.5 to 5 mg of vitamin B7.

[0229] In a particular embodiment, a composition is provided comprising: (i)DHA and EPA; (ii) Vitamin D3; (iii) Vitamin B2; (iv) Choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; (v) Dietary fiber and / or dietary butyrate; (vi) Vitamin B6; (vii) Vitamin B9; and at least one or more of the following ingredients: (viii) Retinol equivalents of vitamin A; (ix) Vitamin B1; (x) Vitamin B12; (xi) Vitamin C; (xii)α-TE; (xiii) Selenium; and (xiv)magnesium (xv) Coenzyme Q10.

[0230] In the most preferred embodiment, the nutritional composition comprises the following combination: i) DHA; the preferred range based on 100 g dry weight of the composition is 480 – 680 mg, more preferably 510 – 650 mg, and most preferably 550 – 610 mg of DHA; ii) Vitamin B2; the preferred range based on 100 g dry weight of the composition is 1.23 – 1.53 mg, more preferably 1.27 – 1.49 mg, and most preferably 1.31 – 1.44 mg; iii) Vitamin D3; the preferred range based on 100 g dry weight of the composition is 38 – 54 µg, more preferably 40 – 52 µg, and most preferably 42 – 50 µg; iv) Choline; preferably 200-370 mg choline, more preferably 230-340 mg choline, and most preferably 250-310 mg choline per 100 g dry weight of the composition; v) Dietary fiber; the preferred range based on 100 g dry weight of the composition is 9.0 – 11.3 g, more preferably 9.2 – 11 g, and most preferably 9.8 – 10.8 g.

[0231] The nutritional composition preferably further comprises EPA, preferably in the range of 100–170 mg, more preferably 110–160 mg, and most preferably 120–150 mg of EPA based on 100 g dry weight of the nutritional composition. Preferably, choline is provided in the form of free choline, choline salts, and / or choline esters, wherein the choline ester is preferably phosphatidylcholine, and more preferably choline is provided in the form of choline salts and phosphatidylcholine. Preferably, at least 1–5 wt% of choline in the nutritional composition is provided in the form of phosphatidylcholine. In a preferred embodiment, the preferred range of choline provided in the form of phosphatidylcholine based on 100 g dry weight of the composition is 5–15 mg, more preferably 6–12 mg, and most preferably 7–10 mg of choline. Preferably, phosphatidylcholine is contained in phospholipids, and the nutritional composition preferably contains 200–290 mg of phospholipids, more preferably 210–280 mg, and most preferably 220–265 mg of phospholipids per 100 g dry weight of the composition. Preferably, the composition is a powder that can be reconstituted with a liquid (preferably water) to obtain a liquid composition.

[0232] In the most preferred embodiment, the nutritional composition comprises, per 100 ml: i) 30 to 240 mg DHA, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; ii) 0.15 – 1.4 mg of vitamin B2, preferably 0.2 – 1.2 mg, more preferably 0.3 – 1 mg of vitamin B2; iii) 6 – 20 µg of vitamin D3, preferably 8 – 18 µg, more preferably 10 – 15 µg of vitamin D3; iv) 30 to 180 mg of choline, preferably 35 to 170 mg, more preferably 40 to 160 mg of choline; v) 0.5 to 4.0 g of dietary fiber, preferably 1.0 to 3.5 g, and most preferably 1.5 to 3.0 g of dietary fiber.

[0233] The nutritional composition preferably further comprises EPA, preferably ranging from 5 to 60 mg per 100 ml of composition, more preferably from 7 to 55 mg, and most preferably from 9 to 50 mg EPA. Preferably, choline is provided in the form of free choline, choline salts, and / or choline esters, wherein the choline esters are preferably phosphatidylcholine, and more preferably choline is provided in the form of choline salts and phosphatidylcholine. The preferred range for choline provided in the form of phosphatidylcholine is 0.5–8 mg per 100 ml of composition, more preferably 1–7 mg, and most preferably 1.5–5 mg choline. Furthermore, phosphatidylcholine is a component of phospholipids, and the nutritional composition preferably contains 20–200 mg of phospholipids per 100 ml of composition, more preferably 40–150 mg of phospholipids, and most preferably 50–100 mg of phospholipids.

[0234] In the most preferred embodiment, based on the total energy content of the nutritional composition, the nutritional composition contains per 100 kcal: i) 30 to 240 mg DHA, preferably 35 to 220 mg, more preferably 40 to 200 mg DHA; ii) 0.1 – 1.4 mg of vitamin B2, preferably 0.2 – 1.2 mg, more preferably 0.15 – 0.5 mg of vitamin B2; iii) 5 – 30 µg of vitamin D3, preferably 8 – 20 µg, more preferably 10 – 17 µg of vitamin D3; iv) 25 to 110 mg of choline, preferably 30 to 105 mg, more preferably 33 to 100 mg of choline; v) 0.5 to 4.0 g of dietary fiber, preferably 1.0 to 3.5 g, and most preferably 1.5 to 3.0 g of dietary fiber.

[0235] The nutritional composition preferably further comprises EPA, preferably 5 to 60 mg, more preferably 7 to 55 mg, and most preferably 9 to 50 mg of EPA per 100 kcal based on the total energy content of the composition. Preferably, choline is provided in the form of free choline, choline salts, and / or choline esters, wherein the choline esters are preferably phosphatidylcholine, and more preferably choline is provided in the form of choline salts and phosphatidylcholine. Based on the total energy of the composition, the preferred range for choline derived from phosphatidylcholine is 0.5–8 mg, more preferably 1–7 mg, and most preferably 1.5–5 mg of choline per 100 kcal. Furthermore, phosphatidylcholine is a component of phospholipids, and based on the total energy of the composition, the nutritional composition preferably contains 20–200 mg of phospholipids per 100 kcal, more preferably 40–150 mg of phospholipids, and most preferably 50–100 mg of phospholipids.

[0236] In the most preferred embodiment, each daily dose of the nutritional composition comprises: i) 100 to 1250 mg DHA, preferably 150 to 1200 mg, more preferably 200 to 1100 mg, and most preferably 250 to 1000 mg; ii) 0.2 to 10 mg of vitamin B2, preferably 0.4 to 8 mg, more preferably 0.8 to 7.6 mg of vitamin B2; iii) 5 to 80 μg of vitamin D3, preferably 6 to 75 μg, more preferably 8 to 70 µg of vitamin D3; iv) 70 to 1300 mg of choline, preferably 80 to 1200 mg, more preferably 100 to 1100 mg of choline, wherein the choline comprises at least phosphatidylcholine and choline salt; v) 2.5 to 12.5 g of dietary fiber, preferably 3 to 12 g, more preferably 3.5 to 11.5 g of dietary fiber.

[0237] The nutritional composition preferably further comprises 40 to 350 mg, more preferably 50 to 300 mg, and even more preferably 60 to 250 mg of EPA daily. In preferred embodiments, the preferred range of choline derived from phosphatidylcholine is 1 to 15 mg choline / day, more preferably 2 to 12 mg choline / day, and even more preferably 3 to 10 mg choline / day. Furthermore, phosphatidylcholine is a component of phospholipids, and the nutritional composition preferably comprises 50 to 350 mg phospholipids / day, more preferably 75 to 300 mg phospholipids / day, and even more preferably 90 to 250 mg phospholipids / day.

[0238] Example To gain a more comprehensive understanding of this disclosure, please refer to the following examples in conjunction with the accompanying drawings.

[0239] Example 1 - Synergy between DHA and EPA, B2 and D3 on neurite outgrowth in PC12 cells PC12 neuronal cell culture To assess the effects of nutrient components on axonal outward growth and dendritic branching, which are fundamental to functional brain connectivity, the influence of nutrient supplementation on neurite outward growth parameters in PC12 pheochromocytoma cells was investigated. The PC12 neuronal cell model is one of the most widely used cell models for studying neuronal differentiation.

[0240] 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 under a humid atmosphere of 95% air and 5% CO2. Cells were grafted at a density of 5000 cells / well into collagen-coated 96-well plates and supplemented with medium containing 20 ng / ml nerve growth factor (NGF) after 24 hours, with or without the components defined in this and subsequent examples. The cell cultures were incubated at 37°C in 5% CO2, with the medium changed every 2–3 days.

[0241] Nutrient supplementation The effects of nutrient supplementation on neuronal PC12 cultures were assessed 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 a mediator control (0 µM). Nutrients were supplemented individually or in combination with each other.

[0242] DHA and EPA were resuspended in anhydrous ethanol and diluted 5-fold in fetal bovine serum. Other compounds were dissolved in DMEM. All compounds were purchased from Sigma (Zwijndrecht, Netherlands). Cells were supplemented in 96-well plates, in six replicates. Neuronal ingrowth under these conditions was compared with that under unsupplemented cells.

[0243] Neurite outgrowth: immunocytochemistry and imaging Forty-eight hours after nutrient supplementation, cell bodies and neurites were stained with calcein-AM staining agent (0.2 µg / ml) (Invitrogen, lot C3100MP) in 100 μl of culture medium per well, and nuclei were counterstained with Hoechst staining agent (1.2 µg / ml) (Thermo Scientific, lot 62249), and incubated at 37°C for 20 min. Subsequently, FITC and DAPI images (9 images per well, 6 wells per condition) were acquired using the ImageXpress miniature confocal high-content imaging system (Molecular Devices). The length of neurites was quantified using the neurite outgrowth module in MetaXpress. Image analysis was performed using the neurite outgrowth analysis module in MetaXpress. Measurements obtained from each well included the number of nuclei and the average neurite outgrowth per cell (µm). The data is normalized relative to the control holes treated with the medium and expressed as a relative percentage of the plate average of the control holes treated with that medium.

[0244] Results Image analysis of neurite outgrowth showed that, in an in vitro PC12 neuron cell model, supplementation with ω-3 fatty acids DHA and EPA, and vitamins B2 and D3 alone increased neurite outgrowth compared to control. Neuron outgrowth is expressed as a percentage relative to control (100%). Furthermore, when combined, neurite outgrowth was improved synergistically: the mean percentage of neurite outgrowth was higher than expected based on the additive effect 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.

[0245] Figure 2 The study was conducted on separate 96-well plates, with DHA (6.7 μM) supplemented as the sole ω-3 fatty acid and vitamin B2 concentrations varying between 0.5 μM and 1 μM, indicating a similar trend toward improved neurite outward growth as compared to the control. Figure 3 Similar effects were observed at DHA concentrations of 3.3 μM and vitamin B2 concentrations varying between 0.5 μM and 1 μM. In summary, these results indicate the presence of effects on neurite outgrowth across a wide concentration range of DHA and vitamin B2.

[0246] It should be noted that interplate comparisons cannot be made because the outward growth of neural processes is a relative measurement compared to a control with mediator supplementation, and therefore only intraplate changes should be considered.

[0247] Example 2 - Choline chloride:PC ratio influences neurite outgrowth in PC12 cells For PC12 neuronal cell cultures and for measuring the outward growth of neurites using immunohistochemistry and imaging, refer to Example 1.

[0248] Nutrient supplementation The effects of nutrient supplementation with different sources of choline by adding chol-Cl or PC to neuronal cultures were evaluated by comparing different molar ratios of choline chloride (chol-Cl) and phosphatidylcholine (PC) with a mediator control (0 μM). Nutrients were supplemented individually (100 mol% chol-Cl or 100 mol% PC) and at molar ratios of chol-Cl:PC of 60:40 and 40:60. Cells were supplemented with choline derived from chol-Cl, PC, or both at a total concentration of 20 µM in six 96-well plates. These conditions were compared with control cells supplemented with the mediator.

[0249] Results Image analysis of neurite outward ingrowth showed that supplementation with 100% PC increased neurite outward ingrowth more significantly than supplementation with 100 mol% CHOL-Cl compared to the control. Furthermore, CHOL-Cl:PC molar ratios of 60:40 to 40:60 showed similar improvements in neurite outward ingrowth compared to the control group and to supplementation with 100 mol% CHOL-Cl. These results are depicted in... Figure 4 middle.

[0250] The results of neurite outward growth studies showed that both choline chloride and PC enhanced neurite outward growth. Choline provided in the combined form of PC and choline slightly enhanced the effect on neurite outward growth.

[0251] Example 3 - Synergy between DHA (and EPA), B2 and D3 and chol-Cl and / or PC on neurite outgrowth in PC12 cells Nutrient supplementation For PC12 neuronal cell cultures and for measuring the outward growth of neurites using immunohistochemistry and imaging, refer to Example 1.

[0252] Results The effects of nutrient supplementation with a combination of chole-Cl, PC, and DHA, B2, and D3 on neurite outgrowth in PC12 cells were evaluated by comparison with a mediator control. PC12 cells were supplemented with the following nutrients: (1) 100% chol-Cl (20 µM choline). (2) 100% PC (20 µM choline). (3) A combination of DHA (3.3 µM), B2 (0.5 µM), and D3 (0.25 µM), (4) A combination of 100% chol-Cl (20 µM), DHA (3.3 µM), B2 (0.5 µM), and D3 (0.25 µM), (5) A 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). (6) A combination of 100% PC (20 µM), DHA (3.3 µM), B2 (0.5 µM) and D3 (0.25 µM).

[0253] In individual experiments, PC12 cells were supplemented with either PC (20 µM, producing 2.8 µM choline), DHA (5 µM) and EPA (1 µM), B2 (0.5 µM) and D3 (0.25 µM), or a combination of PC (20 µM), DHA (5 µM) and EPA (1 µM), B2 (0.5 µM) and D3 (0.25 µM).

[0254] Under 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 with those without supplementation.

[0255] Figure 5 Similarly, image analysis of neurite outward growth showed that, compared to the control, supplementation with 100% PC increased neurite outward growth more than supplementation with 100 mol% chol-Cl. Furthermore, the combination of DHA, B2, and D3 beneficially further increased neurite outward growth.

[0256] Surprisingly, the combination of 100 mol% chol-Cl with DHA, B2, and D3 synergistically increased neurite outgrowth to a greater extent than predicted based on the additive effects of chol-Cl alone and the combination of DHA, B2, and D3 (calculated or expected mean neurite outgrowth of 122.9 vs. observed mean neurite outgrowth of 127.7). The same effect was observed with the combination of 100 mol% PC with DHA, B2, and D3 (calculated or expected mean neurite outgrowth of 129.8 vs. observed mean neurite outgrowth of 134.3). At a chol-Cl to PC molar ratio of 20:80, the synergistic effect with the combination of DHA, B2, and D3 remained (observed mean neurite outgrowth of 135.2). These results are described in… Figure 6 middle.

[0257] also, Example 4 - BA promotes neurite outgrowth in PC12 cells in a dose-dependent proportional effect The effects of PC combined with DHA and EPA, B2, and D3 on neurite outgrowth in PC12 cells were demonstrated. Similarly, synergistic effects were observed when comparing the effects of PC alone with the combination of DHA, EPA, B2, and D3 (calculated or expected mean neurite outgrowth was 130.7, and observed mean neurite outgrowth was 136.3).

[0258] These results indicate that when combined with chole-Cl or PC, there is improved neurite outgrowth, and this effect exists within the DHA concentration range and also in the presence of EPA as ω-3 FA.

[0259] Nutrient supplementation For PC12 neuronal cell cultures and for measuring the outward growth of neurites using immunohistochemistry and imaging, refer to Example 1.

[0260] Results The nutrient supplementation effect of butyrate (BA) in neuronal cell cultures was evaluated by comparing different concentrations of butyrate (BA) (12.5 µM, 25 µM, 50 µM, 100 µM, and 200 µM) with a mediator control (0 μM). Cells were supplemented in 96-well plates, in six replicates. These conditions were compared with unsupplemented cells.

[0261] Figure 7 Image analysis of neurite outward growth showed that BA supplementation increased neurite outward growth in a dose-dependent manner. The results are depicted in... Example 5 - Synergy between DHA, B2, D3, PC and BA on neurite outgrowth in PC12 cellsA dose-response effect was observed, with the strongest effect on neurite outward growth observed at a concentration of 200 μM BA.

[0262] Nutrient supplementation For PC12 neuronal cell cultures and for measuring the outward growth of neurites using immunohistochemistry and imaging, refer to Example 1.

[0263] Results The effects of nutrient supplementation with BA, B2, DHA, D3, and PC, or combinations thereof, were evaluated in neuronal cultures by comparison with a mediator 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.

[0264] Several conditions were studied, and PC12 cells were supplemented with the following: (1) BA only (2) B2 only (3) DHA only (4) D3 only (5) PC only (6) DHA + B2 + D3 (7) BA + DHA + B2 + D3 (8) PC + DHA + B2 + D3 (9) BA + PC + DHA + B2 + D3 Cells were replenished in 96-well plates, in six replicates. These conditions were then compared with those of unreplenished cells.

[0265] Figure 8 Image analysis of neurite outgrowth showed that in an in vitro PC12 neuron 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. Neuron outgrowth is expressed as a percentage relative to the control (100%). Results are depicted in... Example 6 - Synergy between B2, D3, BA and PC and a reference diet middle.

[0266] Surprisingly, the combined nutrient supplementation had a greater effect on neurite outgrowth than the sum of the individual effects of the nutrients. The combination of DHA with B2 and D3 (condition (6)) produced a synergistic effect on neurite outgrowth (calculated or expected mean neurite outgrowth of 132.4, observed mean neurite outgrowth of 138.3). When the nutrients in the latter condition were combined with BA, even more synergistic effects were observed (condition (7); calculated or expected mean neurite outgrowth of 146.6, observed mean neurite outgrowth of 149.2). A similar effect was observed when PC was supplemented with DHA, B2, and D3 (condition (8); calculated or expected mean neurite outgrowth of 143, observed mean neurite outgrowth of 152.8). Supplementing PC12 cells with all five components together increased neurite outgrowth more than predicted based on individual components, indicating a synergistic effect between BA + DHA + PC + B2 + D3 (condition (9); calculated or expected mean neurite outgrowth was 157.2, observed mean neurite outgrowth was 167.2).

[0267] Overall, the results indicate that the combination of DHA, B2, and D3 synergistically increases neurite outward growth, and this also applies when PC and / or BA are added to the combination.

[0268] Nutrient supplementation For PC12 neuronal cell cultures and for measuring the outward growth of neurites using immunohistochemistry and imaging, refer to Example 1.

[0269] Results The effects of nutrient supplementation with vitamin B2, vitamin D3, PC, and BA alone, or in combination with a reference diet, were evaluated in neuronal cultures by comparison with a mediator control. The concentrations of B2, D3, PC, and BA on the first plate were 0.25 µM, 0.75 µM, 15 µM, and 40 µM, respectively. The effects of supplementation with B2 (0.25 µM), D3 (0.75 µM), and BA (200 µM) on the second plate, or in combination with a reference diet, were evaluated. The reference diet on both plates contained the following components: PC (5 µM), DHA (2 µM), choline chloride (4 µM), vitamin C (15 µM), vitamin E (4 µM), vitamin B6 (2 µM), vitamin B9 (3 µM), vitamin B12 (0.02 µM), and selenium (0.016 µM). The mol% ratio of choline chloride to PC in the reference diet was approximately 45:55. Therefore, the combination of dietary and supplemental B2, D3, PC and BA on the first board resulted in a total PC amount of 20 µM and a mol% ratio of choline chloride to PC of approximately 17:83.

[0270] Cells were replenished in 96-well plates, in six replicates. These conditions were then compared with those of unreplenished cells.

[0271] Figure 9 Image analysis of neurite outgrowth showed that, in an in vitro PC12 neuron cell model, supplementation with B2, D3, PC (15 µM), and BA (40 µM) increased neurite outgrowth compared to control. Neuron outgrowth is expressed as a percentage relative to control (100%; dashed line). Furthermore, supplementation with these components, in conjunction with a reference diet, produced a synergistic effect (calculated or expected mean neurite outgrowth of 126.4, observed mean neurite outgrowth of 142.6). These results demonstrate… Figure 10 middle.

[0272] Image analysis of the second plate showed a similar trend, with an unexpectedly strong synergistic effect when nutrient supplementation with B2, D3, and BA (200 µM) was combined with the reference diet (calculated or expected mean neurite outgrowth was 147.8, observed mean neurite outgrowth was 170). See [link to relevant documentation]. Conclusion .

[0273] Example 7 - Functional neurological recovery after acute focal brain injury in rats The aim of these experiments was to observe whether the addition of nutrients B2, D3, PC, and BA improved neurite outgrowth compared to a reference diet containing all individually known beneficial components for neuronal function and development. Surprisingly, when administered in conjunction with the reference diet, the aforementioned components strongly increased neurite outgrowth, exceeding the effects expected based on their other properties.

[0274] Study groups Diet Aged male Wistar rats (n = 27; 14 months old) were housed in a 12-hour light-dark cycle with free access to water and food. All animals were fed a control diet for 4 weeks prior to surgery. Animals were assigned to one of three groups, each consisting of 9 animals: 1) Brain injury and control diet 2) Brain injury and active diet 3) Sham injury and control diet.

[0275] Experimental setup Animals were given a 51-day control diet and / or an active diet, both of which were isocaloric and contained the same amounts of macronutrients (e.g., protein, carbohydrates, and total fat). Additionally, 5 g / 100 g of dietary fiber was included as dietary fiber in both diets. Furthermore, the active diet was similar to the control diet but further fortified as shown in Table 1 below for comparison.

[0276] Table 1. Nutrient supplementation of the control diet relative to the active diet.

[0277]

[0278] Rats can synthesize vitamin C themselves, therefore the control diet did not contain any added vitamin C as part of their daily recommended intake. Furthermore, the active diet contained 81% choline (based on its molecular weight) derived from choline chloride and 19% from PC.

[0279] Results Prior to surgery, animals were anesthetized with 2%–3% isoflurane in 95% O2 and transferred to a stereotaxic apparatus. As a control group, the sham injury consisted of an incision in the skin to expose the skull. For subjects in the study group, an incision was made in the skin to expose the skull, and four holes were drilled in the skull on the right side of the brain, located at the following coordinates relative to the anterior fontanelle and midline: a) AP + 3.5 mm, ML 2.8 mm b) AP + 2 mm, ML 2.8 mm, c) AP + 0.5 mm, ML 2.8 mm and d) AP -1 mm, ML 2.8 mm.

[0280] Regional brain injury was induced by injecting endothelin-1 (Sigma-Aldrich, E7764) at each of four sites using a microinjection pump (CMA / 102, from CMA Microdialysis, AB, Sweden) at a concentration of 0.25 µg / 0.5 µL, for a total volume of 0.5 µL. The injury corresponded to the right sensorimotor cortex region, resulting in persistent impairment of somatosensory and motor function, thus allowing for longitudinal behavioral studies. Following sham injury or brain injury surgery, the skin was sutured and the rats were returned to their cages.

[0281] Animals were housed for 51 days post-surgery and underwent various behavioral tests to assess loss and recovery of functional abilities. To assess overall neurological impairment, the Modified Neurological Impairment Severity Scale (mNSS) was performed weekly at baseline and for 7 weeks post-surgery. The mNSS is a comprehensive score that considers motor, reflex, and balance functions (see Table 2). Two animals that failed to complete the task at baseline were excluded from the analysis. To assess proficient movement, a foot slip test was performed on a horizontal ladder on day 51 post-surgery. Animals were placed on a ladder 30 cm above the ground, and foot misalignment was measured whenever the left hind paw extended below the grid as the rat traversed the ladder.

[0282] Table 2. Modified Neurological Injury Severity Scoring Scale

[0283] Figure 11 The mNSS results showed a significant overall effect in the treatment group (F(2, 22) = 103, p < 0.001), a significant overall effect over time (F(7, 154) = 42.27, p < 0.001), and a significant interaction between treatment and time (F(14, 154) = 4.75, p < 0.001). This implies that the effect shown in the treatment group was significant because the groups showed differences in neurological damage; there was a significant effect over time (weeks) because the mNSS score decreased over time; and there was an interaction between the study groups and time (weeks) because the changes over time differed among the three study groups (see [link to study group]). Figure 11Sidak multiple comparison tests showed that, compared with the group that underwent brain injury but was given a control diet, animals that underwent brain injury and were given an active diet had significantly reduced neurological deficits at weeks 4 and 5 post-injury (see [link to study]). Figure 12 of (Location).

[0284] Foot slip test results showed a significant difference in left hind paw slippage between groups (F(2,18) = 5.041, p<0.02). Tukey's post-operative test showed that on day 51 post-surgery, animals that had undergone brain injury and were fed a control diet were more prone to foot slippage than the control group (sham injury and fed a control diet) and the group that had undergone brain injury and were fed an active diet. This suggests that the active diet restored the skill impairment induced by localized brain injury. Example 8 - Tube-feeding formulation ).

[0285] These results indicate that recovery from acute focal brain injury improves over time when nutrients are supplemented in an active diet. In particular, the active diet supports functional recovery after brain injury, leading to better and faster neurological recovery.

[0286] Example 9 - Oral nutritional supplement An exemplary enteral tube feed was formulated, containing 128 kcal per 100 ml, and 4.88 g of protein, 4.5 g of lipids, and 9.3 g of carbohydrates per 100 kcal. The tube feed contains the ingredients according to Table 1 and is intended for administration via tube to patients following neurological trauma, during recovery from a diagnosis of neurodegenerative disease, or during recovery from brain injury.

[0287]

[0288] ​ An exemplary oral nutritional supplement was formulated, containing 240 kcal per 100 ml, and 6 g of protein, 3.89 g of lipids, and 9.57 g of carbohydrates per 100 kcal. The supplement contains the ingredients according to Table 2 and is intended to be administered as a beverage to patients following nerve trauma, during recovery from a diagnosis of neurodegenerative disease, or during recovery from brain injury.

[0289] .

Claims

1. A nutritional composition comprising the following therapeutically effective combination: i) ω-3 fatty acids, wherein the ω-3 fatty acids contain at least DHA; ii) Vitamin B2; and iii) Vitamin D3, and one or more of the following: iv) choline or its salts and / or phosphatidylcholine; and v) Dietary fiber and / or dietary butyrate, This nutritional composition is intended for use in the treatment of neurodegenerative diseases and / or neurotrauma and / or cerebral palsy, preferably for use in the treatment of neurodegenerative diseases and / or neurotrauma, brain injury and / or brain damage and / or cerebral palsy. The recommended daily intake of vitamin D3 is 5 to 80 μg.

2. The nutritional composition for use according to claim 1, wherein at least 40 mol% of choline is provided in the form of phosphatidylcholine, preferably in a molar ratio of choline or its salt to PC in the range of 40:60 to 60:

40.

3. The nutritional composition for use according to any one of claims 1-2, wherein the nutritional composition further comprises one or more components selected from vitamins A, C and E, phospholipids, selenium, magnesium and other B vitamins.

4. The nutritional composition for use according to any one of the preceding claims, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, and Lewy body dementia.

5. The nutritional composition for use according to any one of the preceding claims, wherein the treatment of the neurodegenerative disease involves, i.e., treating and / or preventing and / or delaying symptoms associated with the neurodegenerative disease in a subject suffering from the neurodegenerative disease, or wherein the subject has been diagnosed with the prodromal phase of the neurodegenerative disease, preferably wherein these symptoms involve, i.e., including one or more of the following: - Cognitive decline associated with memory loss, reduced attention span, decreased executive function, and impaired ability to perform daily activities; and / or - Motor symptoms associated with tremor, rigidity, bradykinesia, coordination, and balance; and / or - Behavioral and psychological changes associated with depression, anxiety, irritability, fatigue, emotional blunting, 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 body temperature regulation.

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

7. The nutritional composition for use according to claim 6, wherein the nerve injury is caused by one or more external factors selected from: - Occupational hazards, including automotive, sports, and workplace accidents; - Explosion and blast damage; -electric shock; - Blunt force trauma; - Penetrating injury, involving an external object, including a bullet or sharp object, that penetrates into the brain, spinal cord, or peripheral nerves.

8. The nutritional composition for use according to any one of claims 1 to 7, wherein the treatment of neurodegenerative diseases involves, i.e., includes, an increase in the outward growth of neurites in a subject with said neurodegenerative disease who is treated with the composition compared to a subject with said neurodegenerative disease who is not treated with the composition, and / or wherein the treatment of neurotrauma involves, i.e., includes, an increase in the length of outward growth of neurons in a subject with said neurotrauma who is treated with the composition compared to a subject with said neurotrauma who is not treated with the composition, preferably wherein the treatment of neurotrauma, brain injury, and / or brain damage includes, compared to a subject with said neurotrauma, brain injury, and / or brain damage who is treated with the composition, an increase in the length of outward growth of neurons in a subject with said neurotrauma, brain injury, and / or brain damage who is treated with the composition.

9. The nutritional composition for use according to any one 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 neurological trauma, preferably after diagnosis of the neurodegenerative disease and / or after diagnosis or occurrence of the neurological trauma, brain injury and / or brain damage.

10. The nutritional composition for use according to any one of the preceding claims, wherein the composition comprises the following daily dose: i) 150 to 1200 mg, preferably 200 to 1100 mg, more preferably 250 to 1000 mg of DHA daily; ii) Vitamin B2 in the range of 0.8 to 7.6 mg, preferably 1 to 7.4 mg, more preferably in the range of 1.2 to 7.2 mg; iii) 6 to 75 μg, preferably 8 to 70 μg, more preferably 10 to 65 μg of vitamin D3; and one or more of the following: iv) Based on the molar weight of choline, 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg of choline, wherein the choline is selected from free choline, choline salts and / or choline esters, preferably at least phosphatidylcholine; and / or (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.

11. 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 tube feed.

12. A nutritional composition comprising, based on 100 g dry weight, the following combination: i) 480 – 680 mg DHA; ii) 1.23 – 1.53 mg Vitamin B2; iii) 38 – 54 µg Vitamin D3; iv) 200 – 370 mg choline; v) 9.0 – 11.3 g dietary fiber, Choline is provided in the form of choline salts and phosphatidylcholine.

13. The nutritional composition of claim 12, wherein the nutritional composition further comprises 100–170 mg of EPA based on 100 g dry weight of the composition.

14. The nutritional composition according to claim 12 or 13, wherein 1 wt% – 5 wt% of choline in the nutritional composition is provided in the form of phosphatidylcholine.

15. A liquid nutrient composition comprising the following: iv) DHA; v) Vitamin B2; vi) Vitamin D3; And from one or more of the following: vii) choline or its salts and / or phosphatidylcholine; and viii) Dietary fiber and / or dietary butyrate.

16. The liquid nutrient composition of claim 15, wherein the composition comprises per 100 kcal: i) 20 to 100 mg, preferably 25 to 90 mg, more preferably 30 to 80 mg DHA; ii) 0.4 to 0.6 mg of vitamin B2; iii) 1.3 to 4.5 μg of vitamin D3; And further includes iv) 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg of choline or its salts and / or phosphatidylcholine; and / or (v) 0.75 to 2.5 g, preferably 1.0 to 2.0 g, more preferably 1.1 to 1.5 g of 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 of dietary butyrate.

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