A lipid emulsion for brain regeneration and optimizing brain development via parenteral or enteral administration

Abstract

The present invention relates to a specific lipid emulsion comprising ≥ 5 % stearidonic acid and ≥ 15 % α-linolenic acid for use in neuroprotection, neuroregeneration and neurodevelopment.

Description

[0001] A lipid emulsion for brain regeneration and optimizing brain development via parenteral or enteral administration

[0002] This application claims the right of priority of European Patent Applications EP24196280.2 filed 23 August 2024, EP25158072.6 filed 14 February 2025, and EP25191935.3 filed 25 July 2025, which are all incorporated by reference herein.

[0003] Field

[0004] The present invention relates to a specific lipid emulsion comprising > 5 % stearidonic acid and > 15 % a-linolenic acid for use in neuroprotection, neuroregeneration and neurodevelopment.

[0005] Background

[0006] We developed Vegaven (VEGA), a novel lipid emulsion for enteral and parenteral (PN) therapy (Lucchinetti E, et al., Am J Clin Nutr, 116(6), 2022). Vegaven is a blend of plant oils including Buglossoides arvensis oil (Ahiflower® oil) that contains high amounts of two shorter chain 18-carbon n- 3 fatty acids, namely a-linolenic acid (ALA) and stearidonic acid (SDA), but a lower amount of the potentially toxic phytosterol stigmasterol than other plant oil-based lipid emulsions. Our detailed comparisons with a soybean oil-based lipid emulsion and a fish oil-based lipid emulsion in the murine PN model revealed that Vegaven possesses unique immunity-enhancing properties (Lucchinetti E, et al., 2022 ibid). In a recent study designed as a direct head-to-head comparison in the PN neonatal piglet model between the novel lipid emulsion Vegaven and a current standard mixed-oil lipid emulsion containing fish oil (SMOF) we unexpectedly observed important beneficial effects of Vegaven on brain health, namely on one of the most important anabolic and regenerative pathways, i.e. insulin signaling (Milstein JL, et al., Mol Metab., 52:101234, 2021). Our findings are unexpected because no PN study so far explored insulin signaling in the brain when using different lipid emulsions. In the PN model, neonatal piglets are exposed to endotoxin released from the PN-induced leaky bowel (Lucchinetti E, et al., Mol Nutr Food Res., 65(5):e1901270, 2021). Our study now demonstrates that Vegaven-fed piglets have lower endotoxin brain tissue concentrations and proinflammatory cytokine levels, and higher IRp (insulin receptor subunit-p) and IRS1 (insulin receptor substrate-1) abundance as well as higher tyrosine phosphorylation of IRS2 (insulin receptor substrate-2), consistent with better preserved insulin action in the brain. A study in rats demonstrated the importance of IRS1 expression in neonatal brain development, specifically hippocampal neurons where it fosters spine maturation and dendrite arborization (Sanchez-Sarasua S, et al., Mol Cell Neurosci., 118:103693, 2022). Accordingly, IRS1 deficiency impairs learning and reduces synaptic plasticity in the rat model (Sanchez-Sarasua S, et al., Brain Struct Funct., 226(1):163-78, 2021). Moreover, IRS2 deficiency in mice was shown to impair brain growth and to promote tau phosphorylation, a signature of neurodegeneration (Schubert M, et al., J Neurosci., 23(18):7084-92, 2003). In fact, there is ample research demonstrating a very tight connection between brain insulin signaling and neurodevelopmental and neurodegenerative disorders (Dierssen M, et al., Front Neurosci., 15:730378, 2021). Brain insulin resistance is a feature of Alzheimer’s disease and strongly associated with cognitive decline (Rhea EM, et al., Aging Dis., 15(4):1688-1725., 2024; Spinelli M, et a!., Front Neurosci., 13:788, 2019; Talbot K, et a!., J Clin Invest., 122(4):1316-38, 2012). Because insulin in the brain also fosters neuron survival, it can be used to treat traumatic brain injury (Shaughness M, et al., Front Neurosci., 14:547175, 2020). In fact, intranasal insulin has been found to alleviate traumatic brain injury (Ding X, etal., Neuroscience, 529:23-36, 2023). Insulin resistance is also linked to delirium in elderly patients with hip fracture (Wang J, et al., Aging Clin Exp Res., 5(7):1521 - 1529, 2023) and increased risk of stroke (Ding PF, et al., Front Endocrinol, 13:1092431 , 2022).

[0007] Based on the above-mentioned state of the art, the objective of the present invention is to provide a lipid emulsion for brain regeneration and optimizing brain development. This objective is attained by the subject-matter of the independent claims of the present specification, with further advantageous embodiments described in the dependent claims, examples, figures and general description of this specification.

[0008] Summary of the Invention

[0009] A first aspect of the invention relates to a lipid emulsion for use in prevention or treatment of neurorelated diseases, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0010] - an omega-3 fatty acid component,

[0011] - an omega-6 fatty acid component,

[0012] - a monounsaturated fatty acid component, and

[0013] - a saturated fatty acid component in the ratios and relationships given in the claims, the detailed description of the invention, and the examples (any % values given throughout this document to be interpreted as mass / mass unless stated otherwise).

[0014] Terms and definitions

[0015] General

[0016] For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

[0017] The terms “comprising”, “having”, “containing”, and “including”, and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open-ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e. , contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of’ or “consisting of.” Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0018] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0019] As used herein, including in the appended claims, the singular forms “a”, “or” and “the” include plural referents unless the context clearly dictates otherwise.

[0020] "And / or" where used herein is to be taken as specific recitation of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and biochemistry, organic synthesis). Standard techniques are used for molecular, genetic, and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (2002) 5th Ed, John Wiley & Sons, Inc.) and chemical methods.

[0022] Any patent document cited herein shall be deemed incorporated by reference herein in its entirety.

[0023] The term fatty acid in the context of the present specification encompasses both a free fatty acid and a fatty acid esterified with glycerol to form a triglyceride. The term triglyceride in the context of the present specification encompasses triglycerides comprising three identical fatty acids, and triglycerides comprising different fatty acids.

[0024] The term TPN in the context of the present specification relates to total parenteral nutrition.

[0025] The term SDA in the context of the present specification relates to stearidonic acid.

[0026] The term ALA in the context of the present specification relates to a-linolenic acid.

[0027] As used herein, the term pharmaceutical composition refers to an emulsion of the invention. In certain embodiments, the pharmaceutical composition according to the invention is provided in a form suitable for parenteral or injectable administration.

[0028] As used herein, the term treating or treatment of any disease or disorder (e.g. neurodegeneration) refers in one embodiment to ameliorating the disease or disorder (e.g. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Methods for assessing treatment and / or prevention of disease are generally known in the art, unless specifically described hereinbelow.

[0029] Detailed Description of the Invention

[0030] A first aspect of the invention relates to a lipid emulsion for use in prevention or treatment of neurorelated diseases. The lipid emulsion was described already in W02024047075, which is incorporated by reference herein.

[0031] The lipid emulsion

[0032] The lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises (all % values as mass / mass):

[0033] - an omega-3 fatty acid component,

[0034] - an omega-6 fatty acid component,

[0035] - a monounsaturated fatty acid component, and

[0036] - a saturated fatty acid component.

[0037] In certain embodiments, the fatty acid of the invention is present as free fatty acid in the emulsion. In certain embodiments, the fatty acid of the invention is present as part of a triglyceride in the emulsion. In certain embodiments, the fatty acid of the invention is present as a mixture of a free fatty acid component and of a triglyceride component in the emulsion. In certain embodiments, the triglyceride component comprises a mixture of different fatty acids.

[0038] The mass of the omega-3 fatty acid component amounts to 20-50 %, the mass of the omega-6 fatty acid component amounts to 3-35 %, the mass of the monounsaturated fatty acid component amounts to 5-40 %, and the mass of the saturated fatty acid component amounts to 5-45 % of the oily phase.

[0039] In certain embodiments, the mass of the omega-3 fatty acid component amounts to 20-40 %, the mass of the omega-6 fatty acid component amounts to 5-25 %, the mass of the monounsaturated fatty acid component amounts to 10-35 %, and the mass of the saturated fatty acid component amounts to 10-40 % of the oily phase.

[0040] In certain embodiments, the mass of the omega-3 fatty acid component amounts to 25-35 %, the mass of the omega-6 fatty acid component amounts to 10-15 %, the mass of the monounsaturated fatty acid component amounts to 18-30 %, and the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase.

[0041] In certain embodiments, the mass of the omega-3 fatty acid component amounts to ~32 %, the mass of the omega-6 fatty acid component amounts to ~12 %, the mass of the monounsaturated fatty acid component amounts to ~27 %, and the mass of the saturated fatty acid component amounts to ~29 % of the oily phase.

[0042] The omega-3 fatty acid component consists of one or more omega-3 (C10-C24 alkyl-oligo-ene carboxylic acids) fatty acids characterized by the presence of more than one carbon double bonds, wherein one carbon-carbon cis double bond is three atoms away from the terminal methyl group (exemplary structure of the omega-3 fatty acid a-linolenic acid (C18:3 omega-3);

[0043] (ALA).

[0044] In certain embodiments, the omega-3 fatty acid component consists of one or several of the members of the group comprised of a-linolenic acid and stearidonic acid.

[0045] The oily phase of the lipid emulsion comprises > 5 % stearidonic acid (C18:4 omega-3) as part of the omega-3 fatty acid component.

[0046] (SDA).

[0047] In certain embodiments, the oily phase of the lipid emulsion comprises ~ 10 % stearidonic acid as part of the omega-3 fatty acid component.

[0048] The oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA) (C18:3 omega-3) as part of the omega-3 fatty acid component.

[0049] In certain embodiments, the oily phase of the lipid emulsion comprises ~ 20 % a-linolenic acid as part of the omega-3 fatty acid component.

[0050] The omega-6 fatty acid component consists of one or more (C10-C24 alkyl-oligo-ene carboxylic acids) omega-6 fatty acids characterized by the presence of more than one carbon double bonds, wherein one carbon-carbon cis double bond six atoms away from the terminal methyl group (exemplary structure of the omega-6 fatty acid linoleic acid (C18:2 omega-6));

[0051] In certain embodiments, the omega-6 fatty acid component consists of one or several of the members of the group comprised of: linoleic acid and y-linolenic acid.

[0052] The monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond.

[0053] In certain embodiments, the monounsaturated fatty acid component comprises or consists of oleic acid (CAS No 112-80-1).

[0054] The saturated fatty acid component consists of one or more fatty acid characterized by no carboncarbon double bond, but only carbon-carbon single bonds. In certain embodiments, the saturated fatty acid component comprises or consists of one or several of the members of the group comprised of: caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and palmitic acid.

[0055] In certain embodiments, the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :5 to 2:1 . In certain embodiments, the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :4 to 1 :1 . In certain embodiments, the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :3 to 1 :2. In certain embodiments, the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is ~1 :2.6.

[0056] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0057] - 30-60 % PUFA (polyunsaturated fatty acid);

[0058] - 5-45 % MUFA (monounsaturated fatty acid); and

[0059] - 5-50 % SFA (saturated fatty acid).

[0060] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0061] - 35-55 % PUFA;

[0062] - 10-40 % MUFA; and

[0063] - 10-45 % SFA.

[0064] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0065] - 40-50 % PUFA;

[0066] - 20-30 % MUFA; and

[0067] - 20-35 % SFA.

[0068] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0069] - ~44 % PUFA;

[0070] - ~27 % MUFA; and

[0071] - ~29 % SFA.

[0072] In certain embodiments, the mass percentages given above relate to the fatty acids as being part of a triglyceride. When calculating the percentages as above, only the mass of the free fatty acid is taken into account, in other words, the percentages are given in relation to the total of fatty acid mass, not considering the mass of any glycerol to which the fatty acids might be esterified. This means that the percentages are given in m% to total mass of fatty acids (which can be esterified or free fatty acids).

[0073] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0074] - 5-35 % stearidonic acid (C18:4 omega-3);

[0075] - 5-50 % oleic acid (C18:1);

[0076] - 2-30 % linoleic acid (C18:2 omega-6);

[0077] - 5-50 % a-linolenic acid (C18:3 omega-3); and - 0.5-15 % Y-linolenic acid (C18:3 omega-6).

[0078] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0079] - 5-25 % stearidonic acid;

[0080] 10-40 % oleic acid;

[0081] - 4-20 % linoleic acid;

[0082] 10-40 % a-linolenic acid; and

[0083] 1-10 % Y-linolenic acid.

[0084] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0085] - 5-15 % stearidonic acid;

[0086] - 20-30 % oleic acid;

[0087] - 5-15 % linoleic acid;

[0088] - 20-30 % a-linolenic acid; and

[0089] - 2-5 % Y-linolenic acid.

[0090] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0091] - ~ 10 % stearidonic acid;

[0092] - ~24 % oleic acid;

[0093] - ~9 % linoleic acid;

[0094] - ~22 % a-linolenic acid; and

[0095] - ~3 % Y-linolenic acid.

[0096] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0097] - 0.5-15 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid (C6:0, C8:0, C10:0);

[0098] 3-35 % lauric acid (C12:0);

[0099] 1-15 % myristic acid (C14:0); and

[0100] 1-20 % palmitic acid (C16:0).

[0101] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0102] 1-10 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0103] - 5-25 % lauric acid;

[0104] - 2-12 % myristic acid; and

[0105] - 3-15 % palmitic acid.

[0106] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0107] - 2-5 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid; 10-15 % lauric acid;

[0108] - 3-8 % myristic acid; and

[0109] - 5-12 % palmitic acid.

[0110] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0111] - ~3.5 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0112] - ~12 % lauric acid;

[0113] - ~4.5 % myristic acid; and

[0114] - ~7.9 % palmitic acid.

[0115] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0116] - 8-50 % olive oil;

[0117] - 8-50 % coconut oil; and

[0118] - 20-90 % Buglossoides arvensis oil (Ahiflower®).

[0119] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0120] 12-40 % olive oil;

[0121] 12-40 % coconut oil; and

[0122] - 30-70 % Buglossoides arvensis oil (Ahiflower®).

[0123] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0124] - 20-30 % olive oil;

[0125] - 20-30 % coconut oil; and

[0126] - 40-60 % Buglossoides arvensis oil (Ahiflower®).

[0127] In certain embodiments, the oily phase of the lipid emulsion comprises:

[0128] - ~25 % olive oil;

[0129] - ~25 % coconut oil; and

[0130] - ~50 % Buglossoides arvensis oil (Ahiflower®).

[0131] In certain embodiments, the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant. In certain embodiments, the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant selected from

[0132] EDTA; and / or

[0133] - alpha tocopherol.

[0134] In certain embodiments, the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant selected from

[0135] ~2.5 pmol / L EDTA; and / or

[0136] -200 mg / L alpha tocopherol. In certain embodiments, the lipid emulsion comprises

[0137] - egg yolk lecithin;

[0138] - glycerol; and

[0139] - water.

[0140] In certain embodiments, the ratio (V / V) between oily phase and aqueous phase ranges between 0.1 to 0.9. In certain embodiments, the ratio (V / V) between oily phase and aqueous phase ranges between 0.2 to 0.8.

[0141] Formulations

[0142] In certain embodiments, the lipid emulsion is formulated for parenteral administration. In certain embodiments, the lipid emulsion is formulated for enteral administration. In certain embodiments, the lipid emulsion is formulated for oral administration. In certain embodiments, the lipid emulsion is administered to a patient for treatment or prevention of one of the indications described below, and wherein this patient requires parenteral or enteral nutrition. In certain embodiments, the lipid emulsion is administered to a patient for treatment or prevention of one of the indications described below, and wherein this patient does not require parenteral or enteral nutrition. In cases where this patient does not require parenteral or enteral nutrition, oral administration might be preferred.

[0143] Indications

[0144] The invention relates to the lipid emulsion described above for use in prevention or treatment of any one of the indications mentioned hereafter.

[0145] In certain embodiments, the indication is prevention or treatment of neurodegeneration or cognitive decline. Imaging with MRI or PET or CT may be used for the detection of neurodegeneration. For a cognitive decline, standardized psychological tests such as the “Mini-Mental Test” can be used to detect a decline in cognitive function.

[0146] In certain embodiments, the indication is prevention or treatment of Alzheimer’s disease. In certain embodiments, the indication is prevention or treatment of Parkinson’s disease.

[0147] In certain embodiments, the indication is prevention or treatment of brain injury. In certain embodiments, the brain injury results after stroke, trauma, radiation, and / or chemotherapy.

[0148] In certain embodiments, the indication is prevention or treatment of delirium. In certain embodiments, delirium results from advanced age, cognitive decline, and / or infection. In certain embodiments, the emulsion is administered to an elderly patient undergoing surgery. The term elderly in the context of the present specification relates to a patient of age > 60. In certain embodiments, the emulsion is administered to a patient in the intensive care unit (ICU). All patients with life-threatening conditions or vital organ dysfunction / failure require intensive care medicine and ICU. Also, many patients after major surgery are transported to ICU for prevention of complication and surveillance. In certain embodiments, the emulsion is administered perioperatively.

[0149] In certain embodiments, the indication is for use in prevention or treatment of brain injury, brain disease or mental retardation. In certain embodiments, the emulsion is administered to a patient of age below (<) 2 years. In certain embodiments, the emulsion is administered to a patient of age < 1 year. In certain embodiments, the emulsion is administered to a preterm (wherein the pregnancy lasted less than 37 weeks) or a neonate (neonate is a child less than 28 days of age). In certain embodiments, the emulsion is administered to a pregnant woman for treatment of the unborn.

[0150] In certain embodiments, the indication is for use in prevention of neurodevelopment impairment. In certain embodiments, the emulsion is administered to a patient of age below (<) 1 year. In certain embodiments, the emulsion is administered to a preterm or a neonate. In certain embodiments, the emulsion is administered to a pregnant woman for treatment of the unborn. Imaging with MRI or PET or CT may be used for the detection of neurodevelopment impairment. In older children and adults, standardized psychological tests can be used to detect a neurodevelopment impairment.

[0151] In certain embodiments, the indication is for use in prevention or treatment of brain dysfunction or cognitive dysfunction. Brain dysfunction or cognitive dysfunction may be characterized by one or more of the following symptoms: incoherent thinking and actions, loss of consciousness, disorientation with regard to time, self-awareness, situation, and location. In certain embodiments, the emulsion is administered to a patient diagnosed with infection, particularly systemic infection. In certain embodiments, the emulsion is administered to a patient diagnosed with sepsis. In certain embodiments, the emulsion is administered to a patient diagnosed with vital organ failure, particularly of the kidney or the liver. Vital organs are the brain, the heart, the lungs, the liver and the kidneys, but more generally also the gut, pancreas, and the immune system.

[0152] In certain embodiments, the indication is promoting neuroprotection. Neuroprotection is needed whenever the nervous system and the brain are exposed to noxious stimuli from internal body-related factors (endogenous) or factors from outside the body (exogenous). Endogenous factors usually are diseases, namely degenerative processes that lead to a decline in the function and ultimately the structure of the brain. These include the diseases of neurodegeneration; the most important ones are Alzheimer’s disease and Parkinson’s disease. Exogenous factors that cause loss of brain function and structure are trauma, toxins (such as those induced by chemotherapy), radiation, and infections. The success of neuroprotection can be objectively measured by neuroimaging such as MRI, CT, PET scans and by psychological tests.

[0153] In certain embodiments, the indication is alleviating symptoms of neurodegeneration. Symptoms of neurodegeneration are complex changes in cognitive capacity (memory function, judgement, and social behaviors), social interactions, and loss of physical capacities such as control of bladder and bowel function, balance, and gate. The improvement of these changes by successful treatment can be easily measured and objectified. They can nowadays also be objectified by neuroimaging (MRI, CT, PET).

[0154] In certain embodiments, the indication is promoting neuroregeneration. Neuroregeneration refers to the body’s capacity to rebuild transiently lost function of the brain by renewing and regenerating the functions and structures of nervous cells and associated tissues. The success of such a treatment can be objectified by simple measurements in the case of a physical capacity (e.g., improved balance or bladder control) or by psychological tests (e.g. improved memory capacity). In certain embodiments, the indication is optimizing and / or improving neurodevelopment.

[0155] Neurodevelopment refers to the brain's life-long amazing capacity to adapt and change to the environment. The normal neurodevelopment can be delayed or negatively affected by diseases (inborn or genetically-caused or by exogenous events, most commonly by infections or diseases of the mother). The period with the most impressive neurodevelopmental changes are during the third trimester of pregnancy and the neonatal period (first 28 days after birth), but continue to be very important for the first two decades of a human life. A successful prevention of negative effects on normal neurodevelopment or a treatment of problems arising from neurodevelopmental disorders can be easily measured by simple measures such as circumference of the head (head size), but nowadays also by sophisticated neuroimaging (MRI, PET).

[0156] In certain embodiments, the lipid emulsion is used in a patient who is characterized by a nuclear phosphorylation level of Ser133 of brain CREB1 (UniProt-ID: P16220) being reduced by > 25% as compared to a reference average phosphorylation level of Ser133 of brain CREB1 in a healthy human population. Nuclear phosphorylation level refers the amount of phosphorylation of CREB1 at position S133 of the protein inside the nucleus of the cell. A healthy human population is a random selection of adult people who do not suffer from any brain disease or brain injury. To determine the average level of phosphorylation, the average is calculated for a population size of at least 100 persons. Reduced by > 25% means that first, the phosphorylation level of the patient and of the healthy human population is determined via determining the amount of CREB1 in the nuclei of brain cells, and the amount of phosphorylated (at S133) CREB1 in the nuclei of brain cells, and dividing the amount of phosphorylated CREB1 by the total amount of CREB1 , yielding a first percentage for the patient and a second percentage for the population. Then, the first percentage is compared to the second percentage, and if the first percentage is lower by at least 25%, the patient is characterized by a nuclear phosphorylation level of Ser133 of brain CREB1 (UniProt-ID: P16220) being reduced by > 25% as compared to a reference average phosphorylation level of Ser133 of brain CREB1 in a healthy human population.

[0157] Pharmaceutical Compositions, Administration / Dosaqe Forms and Salts

[0158] Similarly, within the scope of the present invention is a method or treating a condition as described above (under the header “Indications”) comprising administering to the patient a lipid emulsion according to the above description.

[0159] Similarly, within the scope of the present invention is a method or treating a condition as described above (under the header “Indications”) associated with incapability of ingesting food in a patient in need thereof, comprising administering to the patient a lipid emulsion according to the above description.

[0160] As used therein, “a condition associated with incapability of ingesting food” can relate to any condition in which the patient is transiently or permanently disabled to receive nutrients by via naturalis, i.e. ingestion. Such conditions include being unconscious including coma, being incapable of swallowing, for example caused by neurological disorders, having a blocked oesophageal passage, for example as a result of trauma, tumour disease or other conditions in which the oesophageal passage is restricted or disabled.

[0161] Indications for total or partial parenteral nutrition encompass a wide range of clinical conditions such as critically ill patients (trauma, surgery, sepsis, shock), patients on home parenteral nutrition because of chronic intestinal failure, cachectic cancer patients, patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis), patients with gastrointestinal obstruction, high-output enterocutaneous fistula, or short-bowel syndrome, (mostly) geriatric patients with acute or chronic debilitating diseases who cannot meet nutritional requirements, and patients with intractable nausea and vomiting (hyperemesis gravidarum). Moreover, malnutrition (calories and / or protein related) is a common health care issue with a high prevalence among hospitalized patients (20-50%) and is clearly linked to higher health care costs because of increased complications, longer hospital stays, and higher use of home health care services. In critically ill patients, supplementary parenteral nutrition to enteral nutrition aiming to satisfy the increased caloric needs under stress is also thought to decrease complication rates and associated health care costs.

[0162] The dosage regimen for the emulsion of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. In certain embodiments, the emulsion of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0163] The emulsion of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892).

[0164] Method of Manufacture and Method of Treatment according to the invention

[0165] The invention further encompasses, as an additional aspect, the use of an emulsion as identified herein for use in a method of manufacture of a medicament for the treatment or prevention of a condition as described above (under the header “Indications”).

[0166] Similarly, the invention encompasses methods of treatment of a condition as described above, comprising administering to a patient in need thereof a therapeutically effective amount of the emulsion, as specified in detail herein.

[0167] Wherever alternatives for single separable features are laid out herein as “embodiments”, it is to be understood that such alternatives may be combined freely to form discrete embodiments of the invention disclosed herein. Thus, any of the alternative embodiments for the lipid emulsion may be combined with any of the alternative embodiments of the administration route and these combinations may be combined with any indication mentioned herein.

[0168] The invention further encompasses the following items.

[0169] Items

[0170] 1 . A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0171] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0172] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0173] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond; a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of neurodegeneration or cognitive decline.

[0174] 2. The lipid emulsion for use according to item 1 , wherein the neurodegeneration or cognitive decline is Alzheimer’s disease or Parkinson’s disease. 3. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0175] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0176] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0177] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0178] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of brain injury.

[0179] 4. The lipid emulsion for use according to item 3, wherein the brain injury results after stroke, trauma, radiation, and / or chemotherapy.

[0180] 5. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0181] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0182] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0183] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0184] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of delirium.

[0185] 6. The lipid emulsion for use according to item 5, wherein the emulsion is administered to an elderly patient undergoing surgery.

[0186] 7. The lipid emulsion for use according to item 5, wherein the emulsion is administered to a patient in the intensive care unit.

[0187] 8. The lipid emulsion for use according to item 5, wherein the emulsion is administered perioperatively.

[0188] 9. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0189] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA); an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0190] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0191] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of brain injury, brain disease or mental retardation.

[0192] 10. The lipid emulsion for use according to item 9, wherein the emulsion is administered to a patient of age below (<) 2 years, particularly < 1 year.

[0193] 11 . The lipid emulsion for use according to item 9, wherein the emulsion is administered to a preterm or a neonate.

[0194] 12. The lipid emulsion for use according to item 9, wherein the emulsion is administered to a pregnant woman for treatment of the unborn.

[0195] 13. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0196] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0197] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0198] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond; a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention of neurodevelopment impairment. The lipid emulsion for use according to item 13, wherein the emulsion is administered to a patient of age below (<) 1 year. The lipid emulsion for use according to item 13, wherein the emulsion is administered to a preterm or a neonate. The lipid emulsion for use according to item 13, wherein the emulsion is administered to a pregnant woman for treatment of the unborn. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0199] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0200] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0201] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0202] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of brain dysfunction or cognitive dysfunction. The lipid emulsion for use according to item 17, wherein the emulsion is administered to a patient diagnosed with an indication selected from the group of infection, sepsis, and endorgan failure of the kidney or the liver. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0203] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA); an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group; - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0204] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in promoting neuroprotection. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0205] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0206] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0207] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0208] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in alleviating symptoms of neurodegeneration.

[0209] 21. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0210] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0211] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0212] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond; a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in promoting neuroregeneration.

[0213] 22. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:

[0214] - an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);

[0215] - an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;

[0216] - a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;

[0217] - a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in optimizing and / or improving neurodevelopment.

[0218] 23. The lipid emulsion for use according to any one of the preceding items, wherein the lipid emulsion is formulated for parenteral administration.

[0219] 24. The lipid emulsion for use according to any one of the preceding items 1 to 22, wherein the lipid emulsion is formulated for enteral or oral administration.

[0220] 25. The lipid emulsion according to any one of the preceding items, wherein the omega-3 fatty acid component consists of one or several of the members of the group comprised of a- linolenic acid and stearidonic acid.

[0221] 26. The lipid emulsion according to any one of the preceding items, wherein

[0222] - the oily phase of the lipid emulsion comprises ~10 % stearidonic acid; and

[0223] - the oily phase of the lipid emulsion comprises ~20 % a-linolenic acid (ALA).

[0224] 27. The lipid emulsion according to any one of the preceding items, wherein the omega-6 fatty acid component consists of one or several of the members of the group comprised of linoleic acid and y-linolenic acid. 28. The lipid emulsion according to any one of the preceding items, wherein the monounsaturated fatty acid component comprises or consists of oleic acid.

[0225] 29. The lipid emulsion according to any one of the preceding items, wherein the saturated fatty acid component comprises or consists of one or several of the members of the group comprised of: caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and palmitic acid.

[0226] 30. The lipid emulsion according to any one of the preceding items, wherein

[0227] - the mass of the omega-3 fatty acid component amounts to 20-40 % of the oily phase;

[0228] - the mass of the omega-6 fatty acid component amounts to 5-25 % of the oily phase;

[0229] - the mass of the monounsaturated fatty acid component amounts to 10-35 % of the oily phase;

[0230] - the mass of the saturated fatty acid component amounts to 10-40 % of the oily phase.

[0231] 31. The lipid emulsion according to any one of the preceding items, wherein

[0232] - the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase;

[0233] - the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase;

[0234] - the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase;

[0235] - the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase.

[0236] 32. The lipid emulsion according to any one of the preceding items, wherein

[0237] - the mass of the omega-3 fatty acid component amounts to ~32 % of the oily phase;

[0238] - the mass of the omega-6 fatty acid component amounts to ~12 % of the oily phase;

[0239] - the mass of the monounsaturated fatty acid component amounts to ~27 % of the oily phase;

[0240] - the mass of the saturated fatty acid component amounts to ~29 % of the oily phase.

[0241] 33. The lipid emulsion according to any one of the preceding items, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :5 to 2:1 .

[0242] 34. The lipid emulsion according to any one of the preceding items, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :4 to 1 :1 .

[0243] 35. The lipid emulsion according to any one of the preceding items, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1 :3 to 1 :2.

[0244] 36. The lipid emulsion according to any one of the preceding items, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is ~1 :2.6.

[0245] 37. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0246] - 30-60 % PUFA;

[0247] - 5-45 % MUFA; and

[0248] - 5-50 % SFA.

[0249] 38. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0250] 35-55 % PUFA;

[0251] 10-40 % MUFA; and - 10-45 % SFA. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0252] - 40-50 % PUFA;

[0253] - 20-30 % MUFA; and

[0254] - 20-35 % SFA. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0255] - ~44 % PUFA;

[0256] - ~27 % MUFA; and

[0257] - ~29 % SFA. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0258] - 5-35 % stearidonic acid;

[0259] - 5-50 % oleic acid;

[0260] - 2-30 % linoleic acid;

[0261] - 5-50 % a-linolenic acid; and

[0262] - 0.5-15 % y-linolenic acid. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0263] - 5-25 % stearidonic acid;

[0264] 10-40 % oleic acid;

[0265] - 4-20 % linoleic acid;

[0266] 10-40 % a-linolenic acid; and

[0267] 1-10 % y-linolenic acid. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0268] - 5-15 % stearidonic acid;

[0269] - 20-30 % oleic acid;

[0270] - 5-15 % linoleic acid;

[0271] - 20-30 % a-linolenic acid; and

[0272] - 2-5 % y-linolenic acid. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0273] - ~10 % stearidonic acid;

[0274] - ~24 % oleic acid;

[0275] - ~9 % linoleic acid;

[0276] - ~22 % a-linolenic acid; and

[0277] - ~3 % y-linolenic acid. 45. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0278] - 0.5-15 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0279] 3-35 % lauric acid;

[0280] 1-15 % myristic acid; and

[0281] 1-20 % palmitic acid.

[0282] 46. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0283] 1-10 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0284] - 5-25 % lauric acid;

[0285] - 2-12 % myristic acid; and

[0286] - 3-15 % palmitic acid.

[0287] 47. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0288] - 2-5 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0289] 10-15 % lauric acid;

[0290] - 3-8 % myristic acid; and

[0291] - 5-12 % palmitic acid.

[0292] 48. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0293] - ~3.5 % of a short-chain fatty acid component selected from caproic, caprylic, and capric acid;

[0294] - ~12 % lauric acid;

[0295] - ~4.5 % myristic acid; and

[0296] - ~7.9 % palmitic acid.

[0297] 49. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0298] - 8-50 % olive oil;

[0299] - 8-50 % coconut oil; and

[0300] - 20-90 % Buglossoides arvensis oil.

[0301] 50. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0302] 12-40 % olive oil;

[0303] 12-40 % coconut oil; and

[0304] - 30-70 % Buglossoides arvensis oil.

[0305] 51. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises: - 20-30 % olive oil;

[0306] - 20-30 % coconut oil; and

[0307] - 40-60 % Buglossoides arvensis oil.

[0308] 52. The lipid emulsion according to any one of the preceding items, wherein the oily phase of the lipid emulsion comprises:

[0309] - ~25 % olive oil;

[0310] - ~25 % coconut oil; and

[0311] - ~50 % Buglossoides arvensis oil.

[0312] 53. The lipid emulsion according to any one of the preceding items, wherein the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant.

[0313] 54. The lipid emulsion according to any one of the preceding items, wherein the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant selected from

[0314] EDTA; and / or

[0315] - alpha tocopherol.

[0316] 55. The lipid emulsion according to any one of the preceding items, wherein the lipid emulsion additionally comprises a stabilizer and / or an anti-oxidant selected from

[0317] - ~2.5 pmol / L EDTA; and / or

[0318] - -200 mg / L alpha tocopherol.

[0319] 56. The lipid emulsion according to any one of the preceding items, wherein the lipid emulsion comprises

[0320] - egg yolk lecithin;

[0321] - glycerol; and

[0322] - water.

[0323] 57. The lipid emulsion according to any one of the preceding items, wherein the ratio (V / V) between oily phase and aqueous phase ranges between 0.1 to 0.9.

[0324] 58. The lipid emulsion according to any one of the preceding items, wherein the ratio (V / V) between oily phase and aqueous phase ranges between 0.2 to 0.8.

[0325] The invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

[0326] Description of the Figures

[0327] Fig. 1 shows study flow diagram. Secondary outcomes included growth, bile flow, metabolism and insulin signaling, fatty acid profiles, liver lipid mediator profile, and safety data. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven; JVC, jugular venous catheter.

[0328] Fig. 2 shows cytokine profile in liver. (A) Interleukin-10 (IL10). (B) lnterleukin-6 (IL6). (C) lnterleukin-6 (IL6) to interleukin-10 (IL10) ratio. (D) Tumor necrosis factor-a (TNFa). (E) Interferon-y (IFNy). ‘significantly different. Bars represent means ± SDs. Dots indicate individual experiments. N=8 per group. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0329] Fig. 3 shows hepatic injury markers. (A) y-glutamyl transferase (GGT). (B) Alkaline phosphatase (ALP). (C) Aspartate aminotransferase (AST). (D) Alanine transaminase (ALT). (E) Bilirubin (total). (F) Bile acids. Bars represent means ± SDs. Dots indicate individual experiments. N=8 per group. There were no differences in the individual injury markers. However, when counting the three highest measurements (O) for each of the six liver parameters (“liver panel”, composite liver injury), 14 counts were observed in SMOF-fed piglets but only 4 counts in Vegaven-fed piglets (SMOF 14 / 18 vs VEGA 4 / 18, P=0.002), suggesting a lower potential for liver injury in Vegaven-fed piglets. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0330] Fig. 4 shows blood glucose control and liver glycogen. (A) Insulin plasma concentration. (B)

[0331] Glucagon plasma concentration. (C) Fructosamine (glycated albumin) plasma load. (D) Liver glycogen content, ‘significantly different. Bars represent means ± SDs. Dots indicate individual experiments. N=7-8 per group. One SMOF sample was excluded from glycogen analysis because of prolonged PN line occlusion overnight. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0332] Fig. 5 shows hepatic insulin signaling. (A) Insulin receptor p-subunit abundance (IRp). (B)

[0333] Insulin receptor substrate-2 (IRS2) abundance. (C) Tyrosine phosphorylation of insulin receptor substrate-2 (pY-IRS2). (D) Ratio of total insulin receptor substrate-2 to tyrosine phosphorylated insulin receptor substrate-2 (pY-IRS2 / IRS2). ‘significantly different. Bars represent means ± SDs. Dots indicate individual experiments. N=7-8 per group. One SMOF sample was excluded from IRS2 and pY-IRS2 analyses because of prolonged PN line occlusion overnight. O.D., optical density; SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0334] Fig. 6 shows pancreatic injury. (A) LPS (endotoxin) tissue accumulation. Note logarithmic scale of x-axis. (B) Interleukin-10 (IL10). (C) lnterleukin-6 (IL6). (D) lnterleukin-6 to interleukin-10 ratio (IL6 / IL10) ratio. (E) Tumor necrosis factor-a (TNFa). (F) Interleukin- I p (IL1 P). ‘significantly different. Bars represent means ± SDs. Dots indicate individual experiments. N=8 per group. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0335] Fig. 7 shows brain LPS levels, neuroinflammation, and insulin signaling. (A) LPS (endotoxin) tissue levels (logarithmic scale). (B) Tumor necrosis factor-a (TNFa). (C) lnterleukin-6 (IL6). (D) Insulin receptor p-subunit (IRp). (E) Insulin receptor substrate-1 (IRS1). (F) Insulin receptor substrate-2 (IRS2). (G) Tyrosine phosphorylated insulin receptor substrate-2 to total insulin receptor substrate-2 (pY-IRS2 / IRS2). Note that tyrosine phosphorylations of insulin receptor p-subunit and insulin receptor substrate-1 were below detection limit, ‘significantly different. Bars represent means ± SDs. Dots indicate individual experiments. N=7-8 per group. One Vegaven sample was excluded from LPS analysis because it was below detection limit. SMOF, parenteral nutrition with mixed-oil lipid emulsion containing fish oil; VEGA, parenteral nutrition with Vegaven.

[0336] Fig. 8 shows blood glucose control, liver histology, and hepatic insulin signaling. (A)

[0337] Fructosamine blood levels after 14 days of parenteral nutrition (PN). (B) Liver histology (H.E. staining). Yellow arrows indicate clusters of extramedullary blood cell formation in neonatal livers. White bar in left lower corner indicates magnification (10 pm). (C) Glycogen content in livers after 14 days of PN. (D) Insulin receptor p-subunit abundance. (E) Insulin receptor substrate-2 (IRS2) abundance. ‘Significantly different. Bars represent means ± SDs. Dots indicate individual experiments. SMOF = female piglets treated with SMOFlipid-based PN for 14 days. VEGA = female piglets treated with Vegaven-based PN for 14 days. N=9 for SMOF, N=10 for VEGA.

[0338] Fig. 9 shows brain LPS concentrations, neuroinflammation, and insulin signaling. (A) LPS

[0339] (endotoxin) tissue concentrations (logarithmic scale). (B) Tumor necrosis factor-a (TNFa). (C) Insulin receptor p-subunit (IRp). (D) Insulin receptor subunit-1 (IRS1). Note that tyrosine phosphorylation of IRp and IRS1 were below detection limit. (E) cAMP- responsive-element-binding-protein-1 (CREB1) immunoblots (nuclear fractions) from frontal cortex. ‘Significantly different. Bars represent means ± SDs. Dots indicate individual experiments. SMOF = female piglets treated with SMOFlipid-based PN for 14 days. VEGA = female piglets treated with Vegaven-based PN for 14 days. N=9 for SMOF, N=10 for VEGA.

[0340] Description of the Tables

[0341] Table 1 shows composition of the lipid emulsions used for PN. Abbreviations: PN, parenteral nutrition; PUFA, polyunsaturated fatty acids; MUFA, monounsaturated fatty acids; SFA, saturated fatty acids.

[0342] Table 2 shows body weight, organ growth, and bile flow. Data are expressed as mean [SD] or median [25th, 75th percentile] for the SMOF and Vegaven groups. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). #, Historical data from reference (Turner JM, et al., JPEN J Parenter Enteral Nutr., 40(7):973-81 , 2016). Abbreviations: BW, body weight; PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0343] Table 3 shows lipid mediators in liver tissue collected on day 14. Measured concentrations (in pg per mg tissue wet weight) of lipid mediators in total liver tissue homogenates. Lipid mediators are listed by their abbreviated names (along with their LIPID MAPS® Structure Database identification number in brackets) and their systematic names. The species found to be differentially abundant are indicated by p-values in boldface. Data are expressed as mean (SD) or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. #, detected in only 4 of 8 piglet samples. ##, detected in only 3 (or less) of 8 piglet samples. §CHEBI, Chemical Entities of Biological Interest (https: / / www.ebi.ac.uk / chebi / init.do)

[0344] Abbreviations: PN, parenteral nutrition; SMOF, piglets that received SMOFlipid-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days; LOQ, limit of quantification.

[0345] Table 4 shows fatty acid composition (% total fatty acids) of brain phospholipids on day 14. Fatty acid composition, expressed as % total fatty acids, of phospholipids isolated from brain samples. Data are expressed as mean (SD) or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SFA, saturated fatty acids; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0346] Table 5 shows blood chemistry. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; GGT, y-glutamyl transpeptidase; PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0347] Table 6 shows blood cell count. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. #, significantly increased as compared to SMOF. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: WBC, white blood cells; RBC, red blood cells; MOV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RWD, red cell distribution width; PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegavenbased PN for 14 days.

[0348] Table 7 shows fatty acid composition of brain triglycerides (% total fatty acids) on day 14. Fatty acid composition (expressed as % total fatty acids) of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days. Table 8 shows fatty acid composition (% total fatty acids) of liver phospholipids on day 14. Fatty acid composition (expressed as % total fatty acids) of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0349] Table 9 shows fatty acid composition (% total fatty acids) of plasma phospholipids on day 14. Fatty acid composition (expressed as % total fatty acids) of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0350] Table 10 shows fatty acid composition of liver triglycerides (% total fatty acids) on day 14. Fatty acid composition (expressed as % total fatty acids) of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $, Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0351] Table 11 shows fatty acid composition of plasma triglycerides (% total fatty acids) on day 14. Fatty acid composition (expressed as % total fatty acids) of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $: Values (range) from the reference sow-fed littermates (N=4). Abbreviations: PN, parenteral nutrition; SMOF, piglets that received the mixed-oil lipid emulsion-based PN for 14 days; VEGA, piglets that received Vegaven-based PN for 14 days.

[0352] Table 12 shows fatty acid composition (% total fatty acids) of brain phospholipids on day 14. Fatty acid composition, expressed as % total fatty acids, of phospholipids isolated from brain samples. Data are expressed as mean [SD] or median [25th, 75th percentile], depending on the underlying data distribution. P-values refer to the comparison SMOF vs. VEGA. $: Values (range) from the reference sow-fed littermates (N=7). Abbreviations: PN, parenteral nutrition; SFA, saturated fatty acids; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; SMOF, piglets treated with SMOFlipid-based PN for 14 days; VEGA, piglets treated with Vegaven-based PN for 14 days. Examples

[0353] In a collaborative effort to optimize lipid therapy, we developed Vegaven (VEGA), a novel lipid emulsion for PN therapy. Vegaven is a blend of plant oils including Buglossoides arvensis oil (Ahiflower® oil) (Table 1) that contains high amounts of two shorter chain 18-carbon n-3 fatty acids, namely a-linolenic acid (ALA) and stearidonic acid (SDA), but a lower amount of the potentially toxic phytosterol stigmasterol than other plant oil-based lipid emulsions. Our detailed comparisons with a soybean oilbased lipid emulsion and a fish oil-based lipid emulsion in the murine PN model revealed that Vegaven possesses a unique combination of superior anti-inflammatory, insulin-sensitizing and immunityenhancing properties.

[0354] This study was designed as a direct head-to-head comparison in the PN neonatal piglet model between the novel lipid emulsion Vegaven and a current standard mixed-oil lipid emulsion containing fish oil (SMOF) that is in common clinical use. The use of a large animal model to assess the effects of Vegaven-based PN on whole body physiology, metabolism, and the immune system allowed us to obtain important preclinical data. The PN-fed piglet with immature organ function akin to late prematurity in humans is considered the state-of-the-art preclinical model to investigate PN-related adverse effects in infants. This model also has the advantage of mimicking impaired organ function in critically ill patients with sepsis and develops PN-associated comorbidities such as liver disease. Hence the piglet model is not only able to address important questions about PN efficacy, but further enables investigation of the safety of Vegaven. Since the immunometabolic phenotype of Vegaven is characterized by elevated antiinflammatory interleukin-10 (IL10) tissue levels in the murine model including the liver, which are mechanistically enhancing insulin signaling and immunity, we hypothesized that the provision of Vegaven would similarly elevate tissue IL10 concentrations during PN in the porcine liver (primary outcome) as seen in the murine model when compared with SMOF. Secondary outcomes included bile flow, blood cell counts and chemistry, metabolic data including insulin signaling, proinflammatory cytokines, tissue lipopolysaccharide (LPS) concentrations as well as essential data on safety including total weight gain on trial, organ weights, and essential fatty acid compositions of the phospholipid and triglyceride fractions in plasma, liver, and brain.

[0355] Example 1: Materials and Methods

[0356] Study Design, piglets, parenteral nutrition, and surgical procedures

[0357] All procedures in this study (AUP00003707) were conducted in accordance with the Canadian Council on Animal Care (CCAC) Guidelines and approved by the University of Alberta Animal Care and Use Committee (ACUC). The study was conducted in a bio-secure swine research facility (Swine Research and Technology Centre of the University of Alberta). Male Duroc Landrace White cross-bred piglets, 4- 5-day-old; and female Duroc Landrace cross-bred sow fed piglets, 3-4 day-old were used for total PN experiments (no enteral nutrition) according to a standardized protocol, as previously reported (Figure 1) (Pauline ML, et al., JPEN J Parenter Enteral Nutr., 47(8): 1038-46, 2023). PN started immediately after placing the jugular vein catheter and was delivered continuously by infusion pump for 14 days. Infusions with isocaloric and isonitrogenous PN solutions varied only with respect to type of lipid emulsion. The target nutrient intake of female piglets was 1 .1 MJ kg1day1, 16 g kg-1day1amino acids, and 10 g kg-1day1lipids, equivalent to a standard human infant dose of 2 g kg-1day1. SMOFlipid (SMOF) was purchased from Fresenius Kabi Canada (Toronto, Canada) and Vegaven (VEGA) was produced with a Shear Jet HL60 (DyHydromatics, Atkinson, NH) and subjected to rigorous quality controls, as previously described in detail (Lucchinetti E, et al., Am J Clin Nutr, 2022 ibid). Piglets were selected randomly from the available litter and assigned to receive either Vegaven- or SMOF-based PN (N=8, each group. N=16 in total). The key features and compositions of the two lipid emulsions are presented in Table 1 . The lipid dose of 10g kg-1 day1 reflected the rapid growth of piglets, equivalent to a standard human infant dose of 2g kg-1 day-1 (Turner JM, et al., 2016 ibid). The lipid emulsions were added to the PN immediately before infusion (all-in-one admixture), as previously described (Wykes LJ, et al., J Nutr., 123(7):1248-59, 1993). PN-fed piglets were individually housed (25°C with 12-hour light / dark cycle), while attached to a swivel system for mobility, and were weighed daily. Broadspectrum antibiotics ampicillin and trimethoprim-sulfadoxine were administered from days 0-4 to prevent line sepsis. After that time, if sepsis was suspected in the presence of fever, lethargy, or vomiting, blood cultures were drawn and antibiotic treatment provided. Blood samples were collected on day 14 after detachment from PN during induction of anesthesia forterminal laparotomy and bile flow measurements. Bile flow was determined by a method previously described (Van Aerde JE, et al., Pediatr Res., 45(2):202-8, 1999). The gallbladder was emptied, the cyst duct ligated, and the common bile duct cannulated with an 8 cm 7-Fr polyurethane catheter. After stabilizing the bile flow for 5 minutes, the bile was collected into pre-weighed vials for 10 min. Bile flow sampling was deemed reliable when there was less than a 10% variation between 3 individual readings, or a total of 6 sample collections has been obtained. After humane euthanasia, organs including liver, spleen, bowel, and brain were excised, weighed, and snap frozen in liquid nitrogen for further analyses. Sow-fed littermates (N=4) of equivalent age served as reference piglets for body weight, organ growth, blood cell counts and chemistry, and fatty acid profiles (safety data).

[0358] Blood cell counts and chemistry

[0359] Blood samples collected on day 14 were sent to a veterinary laboratory for automated blood cell counts and biochemistry tests (IDEXX, Edmonton, Canada) including y-glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate aminostranferase (AST), total bilirubin, total bile acids, alkaline phosphatase (ALP), creatinine, glucose, blood urea nitrogen (BUN). In addition, C-reactive protein (CRP; Aviva Systems Biology #GKIA00116) and a-amylase activity (Abeam #ab102523) were measured using commercially available kits.

[0360] Insulin, glucagon, and fructosamine (glycated albumin)

[0361] Plasma insulin (Mercordia #10-1200-01) and glucagon (R&D Systems #DCG0) were assayed using blood collected in heparin-coated tubes supplemented with aprotinin (MilliporeSigma #10820 @ 250U / ml whole blood) and dipeptidyl peptidase-4 inhibitor (MilliporeSigma #DPP4-M @ 10pl / mL whole blood to yield 50 pM final concentration), using the quoted porcine-specific ELISA kits. Fructosamine (Aviva Systems Biology #OKEH02616) levels in heparin plasma were also determined to probe glycemic control during the study period in piglets.

[0362] Glycogen content in liver samples was measured using a glycogen assay kit #MAK016 (MilliporeSigma) in males and a commercially available kit (Abeam #ab65620) in females. Total tissue insulin receptor p- subunit (Cell Signalling #7069C) and IRS1 (Cell Signalling #7328C) as well as their corresponding tyrosine phosphorylation were measured using commercial ELISA kits (Thermo Fisher Scientific #KHR911 1 & KHR9121 ; Cell Signaling #7328 & #7133). IRS2 and its tyrosine phosphorylation were measured using in-house ELISAs, as previously described (Lucchinetti et al., J Nutr, 155(3), 703-718, 2025; Lucchinetti E, et al., 2022 ibid). cA MP-responsive-elem ent-binding-protein- 1 ( CREB 1) imm uno blots

[0363] Nuclear fractionation was obtained by differential centrifugation. Immunoblots for CREB1 pSer133 (Catalogue #28792-1 -AP) and total CREB1 (Catalogue #67927-1 -AP) were carried out using commercial antibodies from Proteintech. Memcode (Thermo Fisher Scientific #24580) staining was used as loading control.

[0364] Cytokine profiling in tissues

[0365] Tissue IL10 (#DY417-05) and interferon-y (IFNy) (#DY485) were measured using R&D Systems Mouse DuoSet ELISA kits that had been prior tested for compatibility and accuracy with porcine samples. Tissue lysates for the R&D Systems DuoSet kits were prepared, as previously described (Lucchinetti E, et al., 2022 ibid). Tissue (homogenized in PBS) interleukin-6 (IL6; Thermo Scientific #ESIL6), tumor necrosis factor-a (TNFa; Thermo Scientific #KSC3011), and interleukin-1 p (IL1 p) (#ESIL1 B) were measured using porcine-specific ELISA kits from Thermo Fisher Scientific. All cytokine measurements were normalized to protein concentration (DC protein assay; Bio-Rad Laboratories).

[0366] Tissue Lipopolysaccharide (LPS, endotoxin) measurements

[0367] Endotoxin levels in tissue (homogenized in PBS) were measured using PyroGene™ Recombinant Factor C endotoxin detection fluorescence kit (Lonza #50-658U; minimum detection limit of 0.005 endotoxin units (EU) / mL) (Lucchinetti E, et al., 2025 ibid; Lucchinetti E, et al., 2022 ibid).

[0368] Fatty acid profiling in phospholipid and triglyceride fractions of plasma, liver, and brain

[0369] Lipids were extracted and analyzed, as previously described (Turner JM, et al., 2016 ibid). Briefly, following extraction using a modified Folch method, phospholipids and triglycerides were separated by thin-layer chromatography, and fatty acids were separated, extracted and methylated, and quantitated by automatic gas-liquid chromatography (Agilent GC model 7890a; Agilent Technology). Individual fatty acids were identified as an area in the chromatogram and calculated as percentage of the total amount.

[0370] Quantitative profiling of lipid mediators in the liver

[0371] Lipid mediators were extracted from frozen liver tissue and screened by ultra-high performance liquid chromatography tandem mass spectrometry, as previously described (Hartling I, et al., Clin Chem Lab Med., 59(11):1811-23, 2021). Statistical analysis

[0372] All results were tested for normality (Shapiro-Wilk test) and summarized as mean (SD) or median (25% percentile, 75th percentile) for the indicated number (N) of independent experiments depending on the underlying data distribution. The significance of differences between Vegaven- and SMOF-based PN groups (direct head-to-head comparison) was determined using a two-tailed Welch's t-test (equal variances not assumed) or Mann-Whitney Rank Sum Test, depending on the data distribution. Differences were considered significant if P<0.05. SigmaPlot (version 15.1.1.26; Grafiti LLC, Palo Alto, CA) was used for all statistical analyses. Sample size calculation was based on estimates calculated a priori using liver IL10 concentrations from our experiments in the murine PN model. Based on measured liver tissue IL10 concentrations of 905 pg / mg protein in the PN group receiving Vegaven and 1043 pg / mg protein in the PN group receiving SMOF (effect size 138 pg / mg protein; unpublished data), and a standard deviation of 80 pg / mg, we estimated a sample size of N=7 piglets per group (two groups with equal enrollment, standard t distribution) with a significance level of 5% and a power of 80%. N=8 piglets per group were enrolled in the study. All other outcomes were considered secondary endpoints and no multiplicity adjustments were applied. Reference ranges from sow-fed littermates were added to presented results including body weight, organ growth, blood cell counts and chemistry, and fatty acid profiles (safety data), but not used for statistical comparison because this study was designed as a direct comparison between SMOF and Vegaven.

[0373] Example 2: Vegaven is well tolerated in neonatal piglets and results in similar gains in body weight and organ growth as compared with SMOF

[0374] All piglets reached the endpoint of the study, i.e., 14 days of total PN (Table 2). Average PN delivery was not different between Vegaven- and SMOF-fed piglets (Table 2). Sepsis was suspected in one case, but could not be confirmed (negative blood cultures). CRP was in the normal range for all piglets at trial end (Table 5). After 14 days of total PN, total body weights were similarly increased in Vegaven- and SMOF-fed piglets as compared with baseline (Table 2). At trial completion, liver and spleen weights, and small bowel lengths and weights, and brain weights were similar in both PN groups (Table 2). Kidney function as measured by creatinine and BUN was similar in both PN groups (Table 5), as well as hemoglobin (g / L) and mean corpuscular hemoglobin (MCH) (Table 6). The percentage of nucleated erythrocytes originating from extramedullary blood formation during the early neonatal phase was higher in blood from Vegaven- than SMOF-fed piglets (Table 6). For additional details of blood cell counts and chemistry, see Table 5 and 6.

[0375] Example 3: Vegaven provides liver protection by increasing IL10 and HOTrEs as compared with SMOF

[0376] IL10 was significantly increased in livers of Vegaven-fed piglets as compared with SMOF-fed piglets (Figure 2A), while IL6 was similar in both groups (Figure 2B). This resulted in a more favorable IL6 / IL10 ratio in livers of Vegaven- vs SMOF-fed piglets (Figure 2C). TNFa was significantly lower in livers of Vegaven-fed piglets as compared with SMOF-fed piglets (Figure 2D). There was a higher IFNy level in livers of Vegaven- than SMOF-fed piglets (Figure 2E), consistent with our previous findings in the murine PN model where higher hepatic IFNy levels were associated with primed T-cells and enhanced immunity (Lucchinetti E, et al., 2022 ibid). Bile flows were not different between the PN groups and comparable with our historical data (Table 2) (Pauline ML, et al., 2023 ibid). Fasting bile acid plasma concentrations were similar between the PN groups, but three out of eight SMOF-fed piglets showed higher concentrations (>25 pmol / L) (Table 5). There was no difference in total bilirubin and GGT between PN groups (Figure 3). However, one piglet in the SMOF group exhibited markedly reduced bile flow (1.32 pg / g / 10 min) combined with higher liver injury markers (bile acid 68.1 pmol / L, bilirubin 21 .8 pmol / L, ALP 1000 pmol / L, AST 105 I U / L, ALT 16 IU / L, GGT 76 I U / L). When counting the three highest measurements for each of the six liver injury markers including GGT, ALP, AST, ALT, bilirubin and bile acids (“liver panel”), 14 counts (O) were observed in SMOF-fed piglets but only 4 counts in Vegaven-fed piglets (Figure 3, SMOF 14 / 18 vs VEGA 4 / 18, P=0.002), suggesting a lower potential for liver injury in Vegaven- vs SMOF-fed piglets. From the 56 lipid mediators measured in total liver tissue, 33 were above the limit of detection and 14 were differentially regulated between the PN groups (Table 3). The ALA metabolites 9S-HOTrE and 13S-HOTrE were elevated in the Vegaven group, whereas some precursors and metabolites of EPA (LTB5), DHA / DPA (19 / 20-EpDPA, 17-HDHA, 14-HDHA), and some oxidation products of ARA (14,15-EET, 5S-HETE, 12-HETE, 15-HETE) and LA (13-HODE, 9-HODE, 12,13- EpOME) were elevated in the SMOF group. For additional details see Table 3.

[0377] Example 4: Vegaven but not SMOF protects against hyperinsulinemia, preserves insulin signaling in the liver, and improves whole-body glucose control

[0378] Plasma insulin concentrations were significantly higher in SMOF- vs Vegaven-fed (Figure 4A), while glucagon levels were similar in both groups (Figure 4B). Hyperinsulinemia as observed in SMOF-fed piglets was accompanied by higher plasma fructosamine (glycated albumin) (Figure 4C), indicating impaired glucose control during the 14-day study period. In accordance with hepatic insulin resistance in SMOF-piglets, liver glycogen content was lower in SMOF- vs Vegaven-fed piglets (Figure 4D). IRp levels in liver tissue were similar between the PN groups (Figure 5A), but a reduced IRS2 level was noted in SMOF-fed piglets (Figure 5B). Lower tyrosine phosphorylation of the IRS2 in liver tissue of SMOF- vs Vegaven-fed piglets was due to the lower abundance of IRS2, resulting in a similar pY- IRS2 / IRS2 ratio (Figure 5C and 5D). Tyrosine phosphorylation of IRp was below the detection limit in both PN groups.

[0379] Example 5: Vegaven prevents LPS accumulation in pancreatic and brain tissue, which is associated with lower inflammation

[0380] Since PN causes gut leakiness and endotoxemia, i.e., LPS release from invasive gut microbiota into the circulation (Lucchinetti E, et al., Mol Nutr Food Res., 2021 ibid; Lucchinetti E, et al., Am J Clin Nutr, 2022 ibid; Lucchinetti E, et al., Clin Nutr ESPEN, 49:278-88, 2022), we wanted to determine LPS accumulation in two key tissues, namely pancreas and brain. LPS was markedly increased (see logarithmic scale) in pancreatic tissue of SMOF-fed piglets (Figure 6A). Accordingly, IL10 was lower (Figure 6B) and IL6 higher (Figure 6C) in pancreatic tissue of SMOF-fed piglets, resulting in a higher IL6 / IL10 ratio (Figure 6D). TNFa and IL1 p levels in pancreatic tissue were also elevated in SMOF-fed piglets (Figure 6E and 6F), and there was a trend to higher a-amylase activity in plasma of SMOF-fed piglets (Table 5). Moreover, LPS was increased in brain tissue of SMOF- vs Vegaven-fed piglets (Figure 7A), which was accompanied by higher TNFa (Figure 7B) and IL6 (Figure 7C) levels. IRp (Figure 7D) and IRS1 (Figure 7E) abundance were lower in brains of SMOF-fed piglets. IRS2 (Figure 7F) abundance was similar in both groups, but consistent with increased pro-inflammatory cytokine levels, there was a lower pY-IRS2 / IRS2 ratio (Figure 7G) in brains of SMOF-fed piglets. Tyrosine phosphorylation of IRp and of IRS1 were below detection limit in both PN groups.

[0381] In the phospholipid fractions of the brains, stearic (24%), palmitic (22.3%) and oleic (16.8%) acids were dominant in both PN groups (Table 4). ARA and DHA were similar between the PN groups. Triene-to- tetraene ratio (MA / ARA ratio), an index of essential fatty acid deficiency if increased, was lower in the brain phospholipid fractions of Vegaven- vs SMOF-fed piglets (Table 4). In the triglyceride fractions of the brains, representing backup and overflow pools of fatty acids from where the phospholipid fractions are continuously remodeled (Tracey TJ, etal., Front Mol Neurosci., 1 1 :10, 2018; Yang C, etal., Neuron, 105(2):276-92, 2020), ARA was higher in Vegaven- vs SMOF-fed piglets (Table 7). In liver phospholipid fractions, stearic (23%), palmitic (17%), and LA (10-13%) were dominant in both groups, but ALA, SDA, y-linolenic acid (GLA), and dihomo-y-linolenic acid (DGLA) were more abundant in Vegaven- vs SMOF- fed piglets (Table 8). As expected from the fatty acid profile of Vegaven, ARA and DHA were lower in the phospholipid fractions of liver and plasma of Vegaven- vs SMOF-fed piglets (Table 8 and 9). MA / ARA ratios were lowest in liver and plasma phospholipid fractions of Vegaven-fed piglets. Notably, compositions of plasma phospholipid fractions did not mirror compositions of brain phospholipid fractions, specifically with regard to ARA and DHA (Table 9 and 8). For additional details of fatty acid compositions in plasma and liver triglyceride fractions see Table 10 and 1 1. Collectively, these data provide evidence of a favorable and balanced fatty acid profile in rapidly growing brains of Vegaven-fed piglets similar to SMOF-fed piglets after two weeks of total PN.

[0382] Example 7: Vegaven improves whole-body glucose control in female piglets by enhancing insulin signaling in the liver as compared with SMOFlipid

[0383] Glucagon plasma concentrations were higher (p=0.045) in SMOFlipid-treated female piglets, which was accompanied with higher (p=0.042) GLP-1 concentrations in SMOFlipid- versus Vegaven-treated female piglets. This hormone profile in SMOFlipid-treated female piglets resulted in higher plasma fructosamine (glycated albumin) (Figure 8A), indicating poorer glucose regulation during the 14-day study period. Histology sections (H.E. staining) of liver samples showed healthy liver architecture with islets of extramedullary blood cell formation, but no infiltration of leukocytes, in both SMOFlipid- and Vegaven-treated female piglets (Figure 8B). There was a trend towards higher glycogen vacuolation in livers of Vegaven-treated female piglets, which was confirmed by higher (p=0.012) glycogen measurements in Vegaven- versus SMOFlipid-treated female piglets (Figure 8C), suggesting increased hepatic insulin sensitivity. IRp (p=0.005) and IRS2 (p=0.002) levels in liver tissue were higher in Vegaven- versus SMOFlipid-treated female piglets (Figure 8D and 8E). Lower tyrosine phosphorylation of the IRS2 in liver tissue of SMOFlipid- versus Vegaven-treated female piglets was due to the lower abundance of IRS2, resulting in a similar pY-IRS2 / IRS2 ratio. Tyrosine phosphorylation of IRp was below the detection limit in both PN groups. Example 8: Vegaven shows evidence of neuroprotection in brains of female piglets as compared with SMOFlipid

[0384] LPS was significantly lower (p=0.009) in brain tissue of Vegaven- versus SMOFlipid-treated female piglets (Figure 9A), which was accompanied by lower concentration of TNFa (p=0.033; Figure 9B) and higher IRS1 abundance (p=0.049; Figure 3C). There was no difference in IRp (Figure 3D) and IRS2 abundance between groups. Tyrosine phosphorylation of IRp and IRS1 were below the detection limit in both PN groups, while tyrosine phosphorylation of IRS2 was similar between groups. Immunoblots of brain nuclear CREB1 , a key transcription factor involved in neurodevelopment, synaptic plasticity, and neuroprotection, showed higher (p=0.022) phosphorylation at Ser133 (pSer133CREB1 / total CREB1) in Vegaven- versus SMOFlipid-treated female piglets (Figure 9E).

[0385] Example 9: Vegaven and SMOFlipid show similar accretion of ARA and DHA in female piglet brains

[0386] In the phospholipid fractions of the brains, stearic (24%), palmitic (22.3%) and oleic (16.8%) acids were dominant in both PN groups (Table 12). ARA and DHA were similar between the PN groups. Triene-to- tetraene ratio (MA / ARA ratio), an index of essential fatty acid deficiency if increased, was similar in the brain phospholipid fractions of Vegaven- vs SMOFlipid-treated female piglets (Table 12). In the triglyceride fractions of the brains (Tracey TJ, et al., Front Mol Neurosci, 2018 ibid; Yang C, et al., Neuron, 2020 ibid), ARA was similar in Vegaven- versus SMOFlipid-treated female piglets. In liver phospholipid fractions, stearic (23%), palmitic (17%), and LA (10-13%) were dominant in both groups, but ALA, SDA, y-linolenic acid (GLA), dihomo-y-linolenic acid (DGLA), EPA, and DPA were more abundant in Vegaven- versus SMOFlipid-treated female piglets. As expected from the fatty acid profile of Vegaven, ARA and DHA were lower in the phospholipid fractions of liver and plasma of Vegaven- versus SMOFlipid-treated female piglets. MA / ARA ratio was lower in liver phospholipid fractions of Vegaven-treated female piglets. Collectively, these data show similar accretion of ARA and DHA after two weeks of total PN in the rapidly growing brains of Vegaven- and SMOFlipid-treated female piglets.

[0387] Example 10: Discussion

[0388] Intravenous administration of lipids containing (essential) fatty acids in patients on PN causes metabolic derangements with insulin resistance, liver inflammation, and immune cell dysfunction (Lucchinetti E, et al., Mol Nutr Food Res., 2021 ibid; Quiroz-Olguin et al., Eur J Clin Nutr, 75(11), 1533-1539, 2021). These conditions are aggravated by changes in the intestinal microbiome and gut barrier dysfunction with leakage of LPS and bacteria into the portal vein and systemic circulation, causing whole-body inflammation (Lucchinetti E, et al., Mol Nutr Food Res., 2021 ibid). Our studies now demonstrate that Vegaven successfully counteracts all these PN-associated adverse effects in male and female piglets alike.

[0389] This study in a relevant preclinical PN neonatal piglet model comparing the currently recommended SMOF- with Vegaven-based PN, shows the following key findings. First, the previously reported unique immunometabolic phenotype with superior biological actions resulting from Vegaven-based PN in the murine model (Lucchinetti E, etal., Am J Clin Nutr, 2022 ibid), was confirmed in this larger animal model. Unlike SMOF, Vegaven is rich in ALA and SDA, generating beneficial octadecanoids (Quaranta A, et al., Biochem Soc Trans, 50 (6): 1569-82, 2022), which upregulate the immune-regulatory cytokine IL10, promote insulin signaling, and display immunity-enhancing effects, namely the attenuation of endotoxemia, as measured by lower LPS accumulation in tissues. In contrast, SMOF-based PN resulted in LPS accumulation with tissue concentrations markedly higher than those measured in Vegaven-fed piglets. SMOF-based PN was accompanied by whole-body insulin resistance and inflammation of liver, pancreas, and brain. Secondly, this study demonstrates that administration of Vegaven is safe in neonatal piglets based on overall end organ growth, blood cell counts and chemistry, and, most importantly, the favorable fatty acid profiles in the rapidly growing brains. The collection of these data on safety will help facilitate a path to Vegaven’s successful clinical application. While we have chosen to compare Vegaven with SMOF, we infer from our current data that the comparison with other mixed- oil lipid emulsions supplemented with fish oil available on the market and differing only slightly from SMOF’s composition, would result in similar findings.

[0390] One piglet in the SMOF group experienced low bile flow with elevated liver injury markers, compatible with the onset of PN-associated liver disease. However, the relatively mild liver involvement caused by 14 days of PN only allowed to observe lower hepatic injury markers more commonly in Vegaven-fed piglets, suggesting liver protection by the increased anti-inflammatory action of IL10. Another PN- associated condition that occurs in more than 40% of patients after 2 weeks of PN is PN-induced pancreatic injury, which is much less investigated (Zhang XM, et al., Nutr Metab (Lond), 19(1 ):73, 2022). While previous studies suggested toxic effects of bile acids on pancreatic duct cells as a possible underlying mechanism (Ferdek PE, et al., J Physiol, 594(21):6147-64, 2016), we observed a high concentration of LPS and inflammation in the pancreatic tissue of SMOF- as opposed to Vegaven-fed piglets. Translocated LPS from gut microbiota into the blood stream, i.e., endotoxemia, results from PN- induced intestinal dysbiosis and gut leakage and it is a well-known trigger of pancreatitis (Del Pozo JL, et al., Pancreatology, 10(2-3):114-8, 2010). Importantly, endotoxemia has been also implicated in the pathogenesis of pancreatic cancer (Sivam HGP, etal., Cancer Biol Ther, 62:361-80, 2023) and diabetes (Musso G, et al., Annu Rev Med, 62:361-80, 2011). Since LPS enhances pancreatic insulin secretion M 1 -like macrophage, it is a likely contributor to the observed hyperinsulinemia and whole-body insulin resistance in SMOF-fed piglets. Conversely, we suspect that improved insulin signaling in Vegaven-fed piglets may have stimulated the proliferation of erythroid progenitor cells (Miyagawa S, et al., Br J Haematol, 109(3):555-62, 2000) and prolonged extramedullary blood formation in the liver, since we observed higher percentages of nucleated erythrocytes in the blood cell counts.

[0391] We reasoned that LPS would also accumulate in other organs such as the brain. Indeed, higher LPS content coupled with increased proinflammatory cytokine levels were detected in the brains of SMOF- fed piglets. Neonatal LPS exposure, i.e. early life stress, has been demonstrated to cause dosedependent, long-lasting adverse effects in the growing brain, specifically the prefrontal cortex and hippocampus, including demyelination, synapse loss, and cognitive decline with alterations in behavior and memory functions (Singh K, et al., Ann Neurosci, 24(3):146-54, 2017; Wang KC, et al., Neuroscience, 234:146-57, 2013). Since LPS exposure to the brain causes neuroinflammation affecting brain insulin actions (Lourenco MV, et al., Cell Metab, 18(6):831 -43, 2013), we determined IRp and IRS1 / 2 abundance and their tyrosine phosphorylation in brain tissues. Of note, insulin is one of the most important anabolic hormones of the body and plays a key role in the development of growing brains (Spinelli M, et al., 2019 ibid). Our study now demonstrates that SMOF-fed piglets have lower IRp and IRS1 abundance, consistent with reduced insulin action in the brain. Both LPS and hyperinsulinemia impair brain insulin actions (Yang X, et al. , Front Neurosci, 16:1036872, 2022), but LPS potentiates hyperinsulinemia’s adverse effects by accelerating insulin’s uptake via the blood brain barrier (Xaio H, et al., Brain Res, 896(1 -2):36-42, 2001). A recent study in rats demonstrated the importance of IRS1 expression in neonatal brain development, specifically hippocampal neurons where it fosters spine maturation and dendrite arborization (Sanchez-Sarasua S, et al., Mol Cell Neurosci, 2022 ibid). Accordingly, IRS1 deficiency impairs learning and reduces synaptic plasticity in the rat model (Sanchez- Sarasua S, etal., Brain Struct Funct, 2021 ibid). Moreover, IRS2 deficiency in mice was shown to impair brain growth and to promote tau phosphorylation, a signature of neurodegeneration (Schubert M, et al., 2003 ibid). While we did not detect differences in brain weights between SMOF- vs Vegaven-fed piglets, more subtle impairments of synapse formation and nerve sprouting may have still occurred (Jung H, et al., Sci Rep, 13(1):6547, 2023). A study comparing brains of SMOF- vs Intralipid-fed preterm piglets showed elevated gene expression of proinflammatory cytokines in brains of Intralipid- as opposed to SMOF-fed piglets (Molina TL, etal., Brain Behav Immun, 85:46-56, 2020). However, no difference in the number of neurons in the prefrontal cortex and hippocampus as well as in exploratory behavior, as a measure of neurodevelopment, were reported. Exposure to LPS with subsequent neuroinflammation and disruption of insulin signaling was further reported to impair ocular function (Faiq MA, et al., Neural Regen Res, 8(5):1139-46, 2023; Ghosh F, et al. , Exp Eye Res, 169:99-110, 2018). We speculate that previously reported differences in retinal function of neonatal piglets fed with PN differing in fatty acid composition, namely ARA and DHA, could be partly due to a varying LPS exposure (Lansing M, et al., JPEN J Parenter Enteral Nutr, 42(7):1177-84, 2018; Turner JM, et al., J Nutr, 146(11):2260-6, 2016). Collectively, additional studies will be necessary to better understand the significance of LPS-mediated neuroinflammation and impaired insulin signaling in growing brains and retinas of PN-fed neonatal piglets.

[0392] Our data show a favorable and balanced fatty acid profile in the rapidly growing brains of Vegaven-fed piglets after two weeks of PN. Pig and human brains accelerate, i.e., triple to quadruple growth from the 3rd trimester to birth, and from birth to the end of the 1st year (pig: 10-30-90g; human: 100-370-1000g). During this critical growth, substantial accretion of ARA and DHA occurs (Hadley KB, et al., Nutrients, 8(4):216, 2016). While in principle these long-chain fatty acids can be formed from their precursors, there are legitimate concerns of insufficient conversion of LA to ARA and ALA to DHA during this rapid growth. Hence, guidelines recommend the addition of preformed ARA and DHA to infant formulas to achieve 0.2-0.4% of total fatty acid provision for DHA and 0.4-0.8% of total fatty acid provision for ARA (Lapillonne A, et al., J Pediatr Gastroenterol Nutr, 69(2):259-70, 2019; Phillips RM, et al., J Perinatol, 33 Suppl 2:S5-22, 2013; Stewart DL, et al., Pediatrics, 144(5), 2019). Unlike SMOF, Vegaven does not contain preformed ARA and DHA, but our fatty acid profiling of the brain phospholipid fractions revealed sufficient and balanced amounts of ARA and DHA in both PN groups. Since Vegaven contains GLA and DGLA precursors of ARA, it is possible that conversion of GLA to ARA may have occurred based on the decreasing GLA / ARA ratios from liver to brain in both the triglyceride and phospholipid fractions. While the liver is most likely the main site of such conversions, it may also occur in the brain itself, mainly by astrocytes (Moore SA, et al., J Mol Neurosci, 16(2-3):195-200, 2001). Our data further show the formation of longer n-3 PUFA in the livers of Vegaven-fed piglets, including ETA, EPA, and DPA from ALA and SDA, respectively, suggesting possible conversion to DHA and transportation to the brains. This is supported by recent findings from a diet switch murine model where Ahiflower oil, an important component of Vegaven, resulted in similar tissue DHA deposition as did dietary fish DHA (Metherel AH, et al., Biochim Biophys Acta Mol Cell Biol Lipids, 1869(1):159422, 2024). Despite the lower ARA and DHA in plasma and liver phospholipid fractions of Vegaven- vs SMOF-fed piglets, we could not detect signs of n-6 or n-3 PUFA deficiency in Vegaven-fed piglets. In fact, mead acid (MA), produced by enzyme competition from oleic acid in the absence of sufficient essential fatty acid precursors and hence an index of essential fatty acid deficiency, as well as triene-to-tetraene ratio (MA / ARA) were consistently lowest in all phospholipid fractions including plasma, liver, and brain of Vegaven-fed piglets. Also, there were no increases in EPA and DHA in the brain phospholipid fractions of Vegaven-fed piglets as one would expect with prolonged ARA deprivation (Igarashi M, et al., J Neurochem, 120(6):985-97, 2012). In fact, ARA was highest in the triglyceride fraction of Vegaven-fed piglet brains, from where continuous remodeling of the phospholipid fraction occurs (Tracey TJ, et al., Front Mol Neurosci, 2018 ibid; Yang C, et al., Neuron, 2020 ibid). Finally, because we found reduced inflammation in liver, pancreas, and brain of Vegaven-fed piglets, we postulate that a reduced consumption of ARA and DHA to generate lipid mediators may have further contributed to the preservation of the ARA and DHA phospholipid pools. Future studies using radioactive tracers will help clarify the significance and dynamics of ARA and DHA consumption in tissues and the potential conversions of their precursors in Vegaven-fed piglets. Irrespectively, Vegaven provided all essential fatty acids, namely ARA and DHA, to the rapidly growing brains of neonatal piglets for as long as two weeks of total PN.

[0393] The fatty acid composition of lipid emulsions and their respective tissue-specific lipid mediator profiles ultimately determine the immunometabolic phenotype. Vegaven elicits a distinct lipid mediator profile characterized by octadecanoids (Quaranta A, et al., Biochem Soc Trans, 2022 ibid). Lower peripheral levels of DHA combined with higher levels of ALA in Vegaven- vs SMOF-fed piglets may indeed lay the ground for Vegaven’s unique phenotype, allowing immune cells to preserve and boost their functional response to infections (Yakah W, et al., Nutrients, 13(1), 2021 ; Rodway LA, et al., Biomed Pharmacother, 159:114167, 2023; Wawrzyniak P, et al., Clin Nutr, 42(12):2422-33, 2023). Our analysis of lipid mediators in the livers of Vegaven-fed piglets now confirms the presence of ALA-derived 9(S)- and 13(S)-HOTrEs, as previously reported in the murine PN model. Mechanistic studies in the murine PN model demonstrated that supplementation of soybean oil-based PN with HOTrEs mimicked many (but not all) features of the immunometabolic phenotype elicited by Vegaven-based PN. As previously shown, Vegaven acts as immunomodulator by priming T-cells (IL10 / IFN-y / IL-17), B-cells (higher levels of anti-LPS immunoglobulins), and macrophages (IL10) to promote host defense during PN (Lucchinetti E, et al., Am J Clin Nutr, 2022 ibid). This action is closely linked to enhanced insulin sensitivity, which by itself, boosts immunity (Tsai S, et al., Cell Metab, 28(6):922-34.e4, 2018). Hence, we postulate that the reduced tissue LPS accumulation and inflammation, as observed in Vegaven-fed piglets, is caused by the strengthened immunity.

[0394] Mechanistic studies in the (male) mouse PN model showed that I L10 directly increased IRS2 abundance in the liver, resulting in improved glucose regulation (Lucchinetti E, etal., 2022 ibid). Although liver tissue cytokine levels including IL10 were generally lower in female versus male piglets as previously reported (Lucchinetti E, et al., 2025 ibid), the IL6 / IL10 ratio was equally favorably decreased in Vegaven- versus SMOFlipid-treated female piglets, providing evidence of lower liver inflammation. Likewise, fructosamine and insulin plasma concentrations in parenterally-fed female piglets were generally lower than in male piglets as previously reported (Lucchinetti E, et al., 2025 ibid), suggesting a more tightly controlled glucose regulation and a possibly greater resilience to insulin resistance in female versus male piglets. However, whole-body glucose control, as measured by fructosamine levels at the end of 14 days of PN, was consistently more favorable in Vegaven- versus SMOFlipid-treated female piglets, similar to what we reported in male piglets (Lucchinetti E, et al., 2025 ibid). Interestingly, while hyperinsulinemia was the hallmark of a less well-controlled glucose regulation in SMOFlipid- versus Vegaven-treated male piglets (Lucchinetti E, et al., 2025 ibid), glucagonemia, i.e. loss of insulin-mediated glucagon suppression (Faerch et al., Diabetes, 65(11), 3473-3481 , 2016), was the outstanding feature in the hormone profile of SMOFlipid- versus Vegaven-treated female piglets. Higher GLP-1 secretion in response to endotoxemia (LPS), as observed in the present study, was previously reported (Nguyen AT, et al., Diabetes, 63(2):471-82, 2014) and is mechanistically involved in the development of hyperinsulinemia. Irrespectively, robust improved whole-body glucose regulation in Vegaven- versus SMOFlipid-treated piglets resulted from enhanced hepatic insulin signaling in both sexes.

[0395] Vegaven specifically acts as immunomodulator by increasing the formation of octadecanoids from 18- carbon n3 fatty acids, such as hydroxy-octadecatrienoic acids (HOTrEs), which prime immune cells creating a cytokine microenvironment with unique anti-inflammatory, but yet immunity-enhancing properties (Kumar et al., Sci Rep, 6, 31649, 2016; Pauls et al., J Nutr Biochem, 57, 121-129, 2018; Pauls et al., Int J Biochem Cell Biol, 119, 105662, 2020; Snodgrass et al., Front Pharmacol, 10, 719, 2019; von Gerichten et al., Front Immunol, 12, 740749, 2021). Previous studies in our PN model with male mice showed that Vegaven specifically affects the gut-microbiome-host interactions by reducing pathogenic bowel-invasive bacteria and thus the release of proinflammatory LPS into the portal vein and systemic circulation(Lucchinetti E, et al., 2022 ibid). LPS-induced whole-body inflammation, a contributing factor to diabetes (Musso G, et al., 2011 ibid), sepsis-induced myopathy (sarcopenia) (Callahan et al., Crit Care Med, 37(10 Suppl), S354-S367, 2009), carcinogenesis (Sivam HGP, et al., 2023 ibid), growth retardation (Hayashi et al., Diabetes, 70(8), 1640-1653, 2021), and impairment of brain development (Singh K, et al., 2017 ibid; Wang KC, et al., 2013 ibid), is further diminished by Vegaven’s ability of boosting the anti-LPS IgG plasma titer and accelerating the lipopolysaccharide- binding protein (LBP)-mediated LPS clearance in the liver(Lucchinetti E, et al., 2022 ibid; Yao et al., J Immunol, 197(6), 2390-2399, 2016), and LPS detoxification by chylomicrons (Lucchinetti E, et al., 2022 ibid; Vreugdenhil et al., J Immunol, 170(3), 1399-1405, 2003). In accordance with these concepts, our study in parenterally-fed female piglets clearly demonstrates marked reductions in LPS accumulation in pancreatic and brain tissues, similar to what we have reported in male piglets (Lucchinetti E, et al., 2025 ibid). Our present study also suggests small bowel edema in SMOFlipid- versus Vegaven-treated female piglets possibly due to inflammation, an observation, which we did not see in male piglets, but this could be due to reported higher baseline intestinal permeability in female sex (Volynets et al., Dig Dis Sci, 61 (3), 737-746, 2016) or sex differences in the gut microbiome (Rosser et al., Front Med (Lausanne), 9, 910561 , 2022). An important finding of our previous comparison of Vegaven versus SMOFlipid in parenterally-fed male piglets was the lower LPS accumulation coupled with reduced TNFa tissue levels and enhanced insulin signaling in the brain of Vegaven-treated piglets. Since neonatal LPS exposure is known to cause long- lasting adverse effects in the growing brain including demyelination, synapse loss, and cognitive decline (Singh K, etal., 2017 ibid; Wang KC, etal., 2013 ibid), our discovery of lower LPS accumulation in brain tissue of Vegaven-treated piglets, now also confirmed in female piglets, emphasizes Vegaven’s potential to robustly protect rapidly growing neonatal brains of either sex during PN. Insulin, one of the most potent anabolic hormones of the body, plays a key role in the development of the brain (Spinelli M, et al., 2019 ibid) as evidenced by a recent study in rats where IRS1 expression in neonatal hippocampal neurons fostered spine maturation and dendrite arborization (Sanchez-Sarasua S, et al., Mol Cell Neurosci, 2022 ibid). In the brains of Vegaven-treated female piglets, we also measured higher phosphorylation at Ser133 of CREB1 , a downstream target of insulin signaling (Klemm et al., J Biol Chem, 273(2), 917-923, 1998) and key regulator of neuronal health via transcriptional activation of many protective genes regulating synaptic growth and memory (Sakamoto et al., J Neurochem, 116(1), 1-9, 2011). n3 PUFA, and specifically so ALA, were shown to upregulate CREB1 phosphorylation (Gao et al., Mol Neurobiol, 53(7), 4772-4786, 2016), notably via PKB / Akt. Increasing the levels of CREB with a viral vector in motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery (Caracciolo et al., Nat Commun, 9(1), 2250, 2018).

[0396] The combination of LPS, neuroinflammation, impaired insulin signaling, and disruption of CREB1 activity also plays a center role in the pathogenesis and progression of neurodegeneration such as Alzheimer’s disease (Brown et al., Mol Neurodegener, 19(1), 30, 2024; Chen et al., Proc Natl Acad Sci U S A, 120(21), e2220684120, 2023; Chen et al., Proc Natl Acad Sci U S A, 122(21), e2501527122, 2025; Lourenco MV, et al., 2013 ibid; Talbot K, et al., 2012 ibid; Bartolotti et al., Mol Psychiatry, 21 (9), U SS- USS, 2016; Jean Gregoire et al., Proc Natl Acad Sci U S A, 121 (49), e2406998121 , 2024 ). According to the endotoxin concept of Alzheimer’s disease, elevated LPS from infections and gut dysfunction, which promotes amyloid pathology, directly contributes to neurodegeneration. Blood and brain levels of LPS are elevated in AD patients, AD risk factors increase LPS levels, LPS induces amyloid, inflammation and neurotoxicity. Our data in parenterally-fed female piglets also confirm a beneficial accretion of the key fatty acids arachidonic acid and docosahexaenoic acid in the rapidly growing neonatal brains.

[0397] In summary, Vegaven proves to be safe and effective in this model of rapidly growing piglets. Vegavenbased PN consistently demonstrates superior biological actions compared with SMOF, namely reduced liver, pancreas, and brain inflammation, and improved insulin signaling and whole-body glucose control.

[0398] Cited references:

[0399] Bartolotti N, Bennett DA, Lazarov O: Reduced pCREB in Alzheimer's disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol Psychiatry 2016; 21 (9):1158-66

[0400] Brown GC, Heneka MT: The endotoxin hypothesis of Alzheimer's disease. Mol Neurodegener 2024; 19(1):30

[0401] Callahan LA, Supinski GS: Sepsis-induced myopathy. Crit Care Med 2009; 37(10 Suppl):S354-67 Caracciolo L, Marosi M, Mazzitelli J, Latifi S, Sano Y, Galvan L, Kawaguchi R, Holley S, Levine MS, Coppola G, Portera-Cailliau C, Silva AJ, Carmichael ST: CREB controls cortical circuit plasticity and functional recovery after stroke. Nat Commun 2018; 9(1):2250

[0402] Chen W, Huang Q, Lazdon EK, Gomes A, Wong M, Stephens E, Royal TG, Frenkel D, Cai W, Kahn CR: Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model. Proc Natl Acad Sci U S A 2023; 120(21):e2220684120

[0403] Chen W, Liu X, Munoz VR, Kahn CR: Loss of insulin signaling in microglia impairs cellular uptake of Abeta and neuroinflammatory response exacerbating AD-like neuropathology. Proc Natl Acad Sci U S A 2025; 122(21):e2501527122

[0404] Del Pozo JL. Primers on molecular pathways: lipopolysaccharide signaling - potential role in pancreatitis and pancreatic cancer. Pancreatology. 2010;10(2-3):114-8. doi: 10.1159 / 000299987.

[0405] Dierssen M, Barone E. Editorial: Brain Insulin Resistance in Neurodevelopmental and Neurodegenerative Disorders: Mind the Gap! Front Neurosci. 2021 ;15:730378. doi: 10.3389 / fnins.2021 .730378.

[0406] Ding PF, Zhang HS, Wang J, Gao YY, Mao JN, Hang CH, Li W. Insulin resistance in ischemic stroke: Mechanisms and therapeutic approaches. Front Endocrinol (Lausanne). 2022;13:1092431 . doi: 10.3389 / fendo.2022.1092431 .

[0407] Ding X, Zhang L, Zhang X, Qin Y, Yu K, Yang X. Intranasal Insulin Alleviates Traumatic Brain Injury by Inhibiting Autophagy and Endoplasmic Reticulum Stress-mediated Apoptosis Through the PI3K / Akt / mTOR Signaling Pathway. Neuroscience. 2023;529:23-36. doi: 10.1016 / j.neuroscience.2023.08.009.

[0408] Faerch K, Vistisen D, Pacini G, Torekov SS, Johansen NB, Witte DR, Jonsson A, Pedersen O, Hansen T, Lauritzen T, Jorgensen ME, Ahren B, Holst JJ: Insulin Resistance Is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation. Diabetes 2016; 65(11):3473-3481

[0409] Faiq MA, Sengupta T, Nath M, Velpandian T, Saluja D, Dada R, Dada T, Chan KC. Ocular manifestations of central insulin resistance. Neural Regen Res. 2023;18(5):1139-46. doi: 10.4103 / 1673-5374.355765.

[0410] Ferdek PE, Jakubowska MA, Gerasimenko JV, Gerasimenko OV, Petersen OH. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake. J Physiol. 2016;594(21):6147-64. doi: 10.1113 / JP272774.

[0411] Gao H, Yan P, Zhang S, Huang H, Huang F, Sun T, Deng Q, Huang Q, Chen S, Ye K, Xu J, Liu L: Long-Term Dietary Alpha-Linolenic Acid Supplement Alleviates Cognitive Impairment Correlate with Activating Hippocampal CREB Signaling in Natural Aging Rats. Mol Neurobiol 2016; 53(7):4772-86

[0412] Ghosh F, Abdshill H, Arner K, Voss U, Taylor L. Retinal neuroinflammatory induced neuronal degeneration - Role of toll-like receptor-4 and relationship with gliosis. Exp Eye Res. 2018;169:99-110. doi: 10.1016 / j.exer.2018.02.002. Hadley KB, Ryan AS, Forsyth S, Gautier S, Salem N, Jr. The Essentiality of Arachidonic Acid in Infant Development. Nutrients. 2016;8(4):216. doi: 10.3390 / nu8040216.

[0413] Hartling I, Cremonesi A, Osuna E, Lou PH, Lucchinetti E, Zaugg M, Hersberger M. Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS / MS. Clin Chem Lab Med. 2021 ;59(11):181 1-23. doi: 10.1515 / cclm-2021 -0644.

[0414] Hayashi T, Kubota T, Mariko I, Takamoto I, Aihara M, Sakurai Y, Wada N, Miki T, Yamauchi T, Kubota N, Kadowaki T: Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus. Diabetes 2021 ; 70(8): 1640-1653

[0415] Igarashi M, Kim HW, Chang L, Ma K, Rapoport SL Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J Neurochem. 2012;120(6):985-97. doi: 10.1111 / j.1471-4159.2011 ,07597.x.

[0416] Jean Gregoire M, Sirtori R, Donatelli L, Morgan Potts E, Collins A, Zamor D, Katenka N, Fallini C: Early disruption of the CREB pathway drives dendritic morphological alterations in FTD / ALS cortical neurons. Proc Natl Acad Sci U S A 2024; 121 (49):e2406998121

[0417] Jung H, Lee D, You H, Lee M, Kim H, Cheong E, Um JW. LPS induces microglial activation and GABAergic synaptic deficits in the hippocampus accompanied by prolonged cognitive impairment. Sci Rep. 2023;13(1):6547. doi: 10.1038 / s41598-023-32798-9.

[0418] Klemm DJ, Roesler WJ, Boras T, Colton LA, Felder K, Reusch JE: Insulin stimulates cAMP-response element binding protein activity in HepG2 and 3T3-L1 cell lines. J Biol Chem 1998; 273(2):917-23

[0419] Kumar N, Gupta G, Anilkumar K, Fatima N, Karnati R, Reddy GV, Giri PV, Reddanna P: 15- Lipoxygenase metabolites of alpha-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate antiinflammatory effects by inactivating NLRP3 inflammasome. Sci Rep 2016; 6:31649

[0420] Lansing M, Sauve Y, Dimopoulos I, Field CJ, Suh M, Wizzard P, et al. Parenteral Lipid Dose Restriction With Soy Oil, Not Fish Oil, Preserves Retinal Function in Neonatal Piglets. JPEN J Parenter Enteral Nutr. 2018;42(7):1177-84. doi: 10.1002 / jpen.1145.

[0421] Lapillonne A, Bronsky J, Campoy C, Embleton N, Fewtrell M, Fidler Mis N, et al. Feeding the Late and Moderately Preterm Infant: A Position Paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2019;69(2):259-70. doi: 10.1097 / MPG.0000000000002397.

[0422] Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, et al. TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's betaamyloid oligomers in mice and monkeys. Cell Metab. 2013;18(6):831-43. doi: 10.1016 / j.cmet.2013.11.002.

[0423] Lucchinetti E, Lou PH, Holtzhauer G, Noureddine N, Wawrzyniak P, Hartling I, et al. Novel lipid emulsion for total parenteral nutrition based on 18-carbon n-3 fatty acids elicits a superior immunometabolic phenotype in a murine model compared with standard lipid emulsions. Am J Clin Nutr. 2022;116(6):1805-19. doi: 10.1093 / ajcn / nqac272.

[0424] Lucchinetti E, Lou PH, Chakravarty A, Marcolla CS, Pauline ML, Wizzard PR, Field CJ, Wine E, Hersberger M, Wales PW, Turner JM, Kramer SD, Zaugg M: The Novel Lipid Emulsion Vegaven Is Well Tolerated and Elicits Distinct Biological Actions Compared With a Mixed-Oil Lipid Emulsion Containing Fish Oil: A Parenteral Nutrition Trial in Piglets. J Nutr 2025; 155(3)703-718

[0425] Lucchinetti E, Lou PH, Lemal P, Bestmann L, Hersberger M, Rogler G, Kramer SD, Zaugg M. Gut microbiome and circulating bacterial DNA ("blood microbiome") in a mouse model of total parenteral nutrition: Evidence of two distinct separate microbiotic compartments. Clin Nutr ESPEN. 2022;49:278- 88. doi: 10.1016 / j.clnesp.2022.03.038.

[0426] Lucchinetti E, Lou PH, Wawrzyniak P, Wawrzyniak M, Scharl M, Holtzhauer GA, Kramer SD, Hersberger M, Rogler G, Zaugg M. Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes. Mol Nutr Food Res. 2021 ;65(5):e1901270. doi: 10.1002 / mnfr.201901270.

[0427] Metherel AH, Klievik BJ, Cisbani G, Smith ME, Cumberford G, Bazinet RP. Blood and tissue docosahexaenoic acid (DHA, 22:6n-3) turnover rates from Ahiflower(R) oil are not different than from DHA ethyl ester oil in a diet switch mouse model. Biochim Biophys Acta Mol Cell Biol Lipids.

[0428] 2024;1869(1):159422. doi: 10.1016 / j.bbalip.2O23.159422.

[0429] Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab. 2021 ;52:101234. doi: 10.1016 / j.molmet.2021 .101234.

[0430] Miyagawa S, Kobayashi M, Konishi N, Sato T, Ueda K. Insulin and insulin-like growth factor I support the proliferation of erythroid progenitor cells in bone marrow through the sharing of receptors. Br J Haematol. 2000;109(3):555-62. doi: 10.1046 / j.1365-2141.2000.02047.x.

[0431] Molina TL, Stoll B, Mohammad M, Mohila CA, Call L, Cui L, et al. New generation lipid emulsions increase brain DHA and improve body composition, but not short-term neurodevelopment in parenterally-fed preterm piglets. Brain Behav Immun. 2020;85:46-56. doi: 10.1016 / j.bbi.2O19.04.031 .

[0432] Moore SA. Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro. J Mol Neurosci. 2001 ;16(2-3):195-200; discussion 15-21. doi: 10.1385 / JMN:16:2-3:195.

[0433] Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med. 2011 ;62:361-80. doi: 10.1146 / annurev-med- 012510-175505.

[0434] Nguyen AT, Mandard S, Dray C, Deckert V, Valet P, Besnard P, Drucker DJ, Lagrost L, Grober J. Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: involvement of the GLP-1 pathway. Diabetes. 2014;63(2):471-82. doi: 10.2337 / db13-0903.

[0435] Pauline ML, Huynh C, Wizzard PR, Nation PN, Field CJ, Wales PW, Turner JM. In parenteral nutrition- fed piglets, fatty acids vary by lipid emulsion and tissue sampled. JPEN J Parenter Enteral Nutr.

[0436] 2023;47(8):1038-46. doi: 10.1002 / jpen.2547. Pauls SD, Rodway LA, Winter T, Taylor CG, Zahradka P, Aukema HM: Alpha-linolenic acid enhances the phagocytic and secretory functions of alternatively activated macrophages in part via changes to the oxylipin profile. Int J Biochem Cell Biol 2020; 119:105662

[0437] Pauls SD, Rodway LA, Winter T, Taylor CG, Zahradka P, Aukema HM: Anti-inflammatory effects of alpha-linolenic acid in M1 -like macrophages are associated with enhanced production of oxylipins from alpha-linolenic and linoleic acid. J Nutr Biochem 2018; 57:121-129

[0438] Phillips RM, Goldstein M, Hougland K, Nandyal R, Pizzica A, Santa-Donato A, et al. Multidisciplinary guidelines for the care of late preterm infants. J Perinatol. 2013;33 Suppl 2(Suppl 2):S5-22. doi: 10.1038 / jp.2013.53.

[0439] Quaranta A, Revol-Cavalier J, Wheelock CE. The octadecanoids: an emerging class of lipid mediators. Biochem Soc Trans. 2022;50(6):1569-82. doi: 10.1042 / BST20210644.

[0440] Quiroz-Olguin G, Gutierrez-Salmean G, Posadas-Calleja JG, Padilla-Rubio MF, Serralde-Zuniga AE: The effect of enteral stimulation on the immune response of the intestinal mucosa and its application in nutritional support. Eur J Clin Nutr 2021 ; 75(11):1533-1539

[0441] Rhea EM, Leclerc M, Yassine HN, Capuano AW, Tong H, Petyuk VA, et al. State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease. Aging Dis. 2024;

[0442] 15(4):1688-1725. doi: 10.14336 / AD.2023.0814.

[0443] Rodway LA, Pauls SD, Pascoe CD, Aukema HM, Taylor CG, Zahradka P. Distinct effects of alphalinolenic acid and docosahexaenoic acid on the expression of genes related to cholesterol metabolism and the response to infection in THP-1 monocytes and immune cells of obese humans. Biomed Pharmacother. 2023;159:114167. doi: 10.1016 / j.biopha.2022.114167.

[0444] Rosser EC, de Gruijter NM, Matei DE: Mini-Review: Gut-Microbiota and the Sex-Bias in Autoimmunity - Lessons Learnt From Animal Models. Front Med (Lausanne) 2022; 9:910561

[0445] Sakamoto K, Karelina K, Obrietan K: CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 2011 ; 116(1 ):1 -9

[0446] Sanchez-Sarasua S, Meseguer-Beltran M, Garcia-Diaz C, Beltran-Bretones MT, EIMlili N, Sanchez- Perez AM. IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis. Mol Cell Neurosci. 2022;118:103693. doi: 10.1016 / j.mcn.2021.103693.

[0447] Sanchez-Sarasua S, Ribes-Navarro A, Beltran-Bretones MT, Sanchez-Perez AM. AAV delivery of shRNA against IRS1 in GABAergic neurons in rat hippocampus impairs spatial memory in females and male rats. Brain Struct Funct. 2021 ;226(1):163-78. doi: 10.1007 / s00429-020-02155-x.

[0448] Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003;23(18):7084-92. doi: 10.1523 / JNEUROSCI .23-18-07084.2003.

[0449] Shaughness M, Acs D, Brabazon F, Hockenbury N, Byrnes KR. Role of Insulin in Neurotrauma and Neurodegeneration: A Review. Front Neurosci. 2020;14:547175. doi: 10.3389 / fnins.2020.547175. Singh K, Patro N, Pradeepa M, Patro I. Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain. Ann Neurosci. 2017;24(3):146-54. doi: 10.1159 / 000477152.

[0450] Sivam HGP, Chin BY, Gan SY, Ng JH, Gwenhure A, Chan EWL. Lipopolysaccharide (LPS) stimulation of Pancreatic Ductal Adenocarcinoma (PDAC) and macrophages activates the NLRP3 inflammasome that influences the levels of pro-inflammatory cytokines in a co-culture model. Cancer Biol Ther. 2023;24(1):2284857. doi: 10.1080 / 15384047.2023.2284857.

[0451] Snodgrass RG, Brune B: Regulation and Functions of 15-Lipoxygenases in Human Macrophages. Front Pharmacol 2019; 10:719

[0452] Spinelli M, Fusco S, Grassi C. Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline. Front Neurosci. 2019;13:788. doi: 10.3389 / fnins.2019.00788.

[0453] Stewart DL, Barfield WD, Committee On F, Newborn. Updates on an At-Risk Population: Late-Preterm and Early-Term Infants. Pediatrics. 2019;144(5). doi: 10.1542 / peds.2019-2760.

[0454] Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122(4):1316-38. doi: 10.1172 / JCI59903.

[0455] Tracey TJ, Steyn FJ, Wolvetang EJ, Ngo ST. Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease. Front Mol Neurosci. 2018;11 :10. doi: 10.3389 / fnmol.2018.00010.

[0456] Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn J J , Chan YT, et al. Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection. Cell Metab. 2018;28(6):922-34 e4. doi: 10.1016 / j.cmet.2O18.08.003.

[0457] Turner JM, Josephson J, Field CJ, Wizzard PR, Ball RO, Pencharz PB, Wales PW. Liver Disease, Systemic Inflammation, and Growth Using a Mixed Parenteral Lipid Emulsion, Containing Soybean Oil, Fish Oil, and Medium Chain Triglycerides, Compared With Soybean Oil in Parenteral Nutrition-Fed Neonatal Piglets. JPEN J Parenter Enteral Nutr. 2016;40(7):973-81 . doi: 10.1177 / 0148607115579711 .

[0458] Turner JM, Sauve Y, Suh M, Wales PW, Wizzard P, Goruk S, Field CJ. A Third-Generation Lipid Emulsion that Contains n-3 Long-Chain PUFAs Preserves Retinal Function in Parenterally Fed Neonatal Piglets. J Nutr. 2016;146(11):2260-6. doi: 10.3945 / jn.116.237669.

[0459] Van Aerde JE, Duerksen DR, Gramlich L, Meddings JB, Chan G, Thomson AB, Clandinin MT. Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets. Pediatr Res. 1999;45(2):202-8. doi: 10.1203 / 00006450-199902000-00008.

[0460] Volynets V, Reichold A, Bardos G, Rings A, Bleich A, Bischoff SC: Assessment of the Intestinal Barrier with Five Different Permeability Tests in Healthy C57BL / 6J and BALB / cJ Mice. Dig Dis Sci 2016; 61 (3):737-46 von Gerichten J, West AL, Irvine NA, Miles EA, Calder PC, Lillycrop KA, Fielding BA, Burdge GC: The Partitioning of Newly Assimilated Linoleic and alpha-Linolenic Acids Between Synthesis of Longer- Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-

[0461] Cell Essential Fatty Acid Metabolism. Front Immunol 2021 ; 12:740749

[0462] Vreugdenhil AC, Rousseau CH, Hartung T, Greve JW, van 't Veer C, Buurman WA: Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J Immunol 2003; 170(3): 1399-405

[0463] Wang J, Shuang P, Li Z, Zhao L, Wang X, Liu P. Association of insulin resistance with delirium and CSF biomarkers of Alzheimer's disease in elderly patients with hip fracture. Aging Clin Exp Res. 2023;35(7):1521-9. doi: 10.1007 / s40520-023-02429-4.

[0464] Wang KC, Fan LW, Kaizaki A, Pang Y, Cai Z, Tien LT. Neonatal lipopolysaccharide exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats. Neuroscience. 2013;234:146-57. doi: 10.1016 / j.neuroscience.2012.12.049.

[0465] Wawrzyniak P, Hubeli B, Wawrzyniak M, Noureddine N, Walberg A, Scharl S, et al. Crosstalk within peripheral blood mononuclear cells mediates anti-inflammatory effects of n-3 PUFA-rich lipid emulsions in parenteral nutrition. Clin Nutr. 2023;42(12):2422-33. doi: 10.1016 / j.clnu.2023.10.016.

[0466] Wykes LJ, Ball RO, Pencharz PB. Development and validation of a total parenteral nutrition model in the neonatal piglet. J Nutr. 1993;123(7):1248-59. doi: 10.1093 / jn / 123.7.1248.

[0467] Xaio H, Banks WA, Niehoff ML, Morley JE. Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res. 2001 ;896(1-2):36-42. doi: 10.1016 / s0006-8993(00)03247-9.

[0468] Yakah W, Ramiro-Cortijo D, Singh P, Brown J, Stoll B, Kulkarni M, et al. Parenteral Fish-Oil Containing Lipid Emulsions Limit Initial Lipopolysaccharide-Induced Host Immune Responses in Preterm Pigs. Nutrients. 2021 ;13(1). doi: 10.3390 / nu13010205.

[0469] Yang C, Wang X, Wang J, Wang X, Chen W, Lu N, Siniossoglou S, Yao Z, Liu K. Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration. Neuron. 2020;105(2):276-92 e5. doi: 10.1016 / j. neuron.2019.10.009.

[0470] Yang X, Xu Y, Gao W, Wang L, Zhao X, Liu G, et al. Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro. Front Neurosci. 2022;16:1036872. doi: 10.3389 / fnins.2022.1036872.

[0471] Yao Z, Mates JM, Cheplowitz AM, Hammer LP, Maiseyeu A, Phillips GS, Wewers MD, Rajaram MV, Robinson JM, Anderson CL, Ganesan LP: Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein. J Immunol 2016; 197(6):2390-9

[0472] Zhang XM, Zhou YQ, Wan YP, Li HJ, Chen ZQ, Song AQ, Tang ML, Xu R, Cai W. The association between parenteral nutrition and pancreatic injury in adult patients: a retrospective observational study. Nutr Meta b (Lo nd). 2022;19(1):73. doi: 10.1186 / s12986-022-00706-z.

[0473] All scientific publications and patent documents cited in the present specification are incorporated by reference herein. Table 1

[0474] Table 2

[0475]

[0476] Table 3

[0477] Table 4

[0478] Table 5

[0479] Table 6

[0480] Table 7

[0481]

[0482] Table 8

[0483] Table 9

[0484]

[0485] Table 10 Table 11

[0486]

[0487] Table 12

[0488]

Claims

Claims1 . A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:- an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA); an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;- a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;- a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of neurodegeneration or cognitive decline.

2. The lipid emulsion for use according to claim 1 , wherein the neurodegeneration or cognitive decline is Alzheimer’s disease or Parkinson’s disease.

3. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises: an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase;o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA); an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;- a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;- a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of brain injury, wherein the brain injury results after trauma, radiation, and / or chemotherapy.

4. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:- an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);- an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group; a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond; a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of delirium.

5. The lipid emulsion for use according to claim 4, wherein the emulsion is administered to an elderly patient undergoing surgery and / or the emulsion is administered to a patient in the intensive care unit and / or the emulsion is administered perioperatively.

6. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises: an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);- an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbondouble bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;- a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond; a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of mental retardation.

7. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises:- an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);- an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;- a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;- a saturated fatty acid component,o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase; o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention and treatment of neurodevelopment impairment.

8. The lipid emulsion for use according to claim 6 or 7, wherein the emulsion is administered to a patient of age below (<) 2 years, particularly < 1 year, more particularly the patient is a preterm or a neonate.

9. The lipid emulsion for use according to claim 6 or 7, wherein the emulsion is administered to a pregnant woman for treatment of the unborn.

10. A lipid emulsion, wherein the lipid emulsion comprises an oily phase and an aqueous phase, wherein the oily phase of the lipid emulsion comprises: an omega-3 fatty acid component, o wherein the mass of the omega-3 fatty acid component amounts to 25-35 % of the oily phase; o wherein the omega-3 fatty acid component consists of one or more omega-3 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond is three atoms away from the terminal methyl group; o and wherein the oily phase of the lipid emulsion comprises > 5 % stearidonic acid; o and wherein the oily phase of the lipid emulsion comprises > 15 % a-linolenic acid (ALA);- an omega-6 fatty acid component, o wherein the mass of the omega-6 fatty acid component amounts to 10-15 % of the oily phase; o wherein the omega-6 fatty acid component consists of one or more omega-6 fatty acids characterized by the presence of more than one carbon-carbon double bonds, wherein one carbon-carbon double bond six atoms away from the terminal methyl group;- a monounsaturated fatty acid component, o wherein the mass of the monounsaturated fatty acid component amounts to 18-30 % of the oily phase; o wherein the monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond;- a saturated fatty acid component, o wherein the mass of the saturated fatty acid component amounts to 20-35 % of the oily phase;o wherein the saturated fatty acid component consists of one or more fatty acid characterized by no carbon-carbon double bond, but only carbon-carbon single bonds for use in prevention or treatment of brain dysfunction or cognitive dysfunction.

11. The lipid emulsion for use according to claim 10, wherein the emulsion is administered to a patient diagnosed with an indication selected from the group of infection, sepsis, and endorgan failure of the kidney or the liver.

12. The lipid emulsion for use according to any one of the preceding claims, wherein the lipid emulsion is formulated for parenteral, enteral or oral administration.

13. The lipid emulsion for use in a patient according to any one of the preceding claims, wherein the patient is characterized by a nuclear phosphorylation level of Ser133 of brain CREB1 being reduced by > 25% as compared to a reference average nuclear phosphorylation level of Ser133 of brain CREB1 in a healthy human population.

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