CN-122003243-A - Microbiome composition for reducing uremic toxins in cardiovascular metabolic or neurodegenerative disorders

Abstract

The present invention relates to compositions, in particular compositions comprising probiotics, prebiotics (carbohydrates or fibers) and lipids, for reducing or avoiding uremic toxin accumulation in cardiovascular metabolic or neurodegenerative disorders.

Inventors

• S. Nutner
• S. Dubux
• A. Pattine
• LAMMERT LOTTE
• C. Lessler
• M. Horman
• J. M.M. natividade
• M. Vonnetten

Assignees

• 雀巢产品有限公司

Dates

Publication Date

20260508

Application Date

20240116

Priority Date

20230118

Claims (20)

1. 1. A composition for reducing or avoiding the accumulation of uremic toxins in cardiovascular metabolic or neurodegenerative disorders, wherein the composition comprises: (a) A probiotic selected from the group consisting of: -lack of genes for the production of at least one of urea, uric acid, p-cresol, p-toluenesulfate, indoxyl sulfate, indole, indoleacetic acid, indoxyl, trimethylamine, TMAO, dimethylglycine, betaine and/or glutaric acid; -lack of at least one bacterial enzyme selected from urease, carnitine monooxygenase and reductase, tryptophan enzyme and/or hydroxyphenylacetate, and/or -Expressing at least one bacterial enzyme selected from the group consisting of alpha-galactosidase, beta-galactosidase, glucan 1, 4-beta-glucosidase, cellulase, beta-fructofuranosidase and/or lichenase; (b) A prebiotic selected from the group consisting of a carbohydrate or fiber, wherein the carbohydrate or fiber is capable of being hydrolyzed by at least one bacterial enzyme selected from the group consisting of alpha-galactosidase, beta-galactosidase, glucan1, 4-beta-glucosidase, cellulase, beta-fructofuranosidase and/or lichenase; (c) A lipid selected from the group consisting of triglycerides, short chain fatty acids and/or medium chain fatty acids, wherein the triglycerides comprise short chain fatty acids, medium chain fatty acids or mixtures thereof.
2. 2. The composition for use according to claim 1, wherein the probiotic (a) is selected from at least one of the following a.to k.: a. Bifidobacterium animalis subspecies lactis NCC 2818 (CNCM I-3446); b. Bifidobacterium longum subspecies infantis NCC 341 (ATCC 15697 (T)); c. Bifidobacterium longum subspecies longum NCC 2705 (CNCM I-2618) (NCBI refseq; GCA_000007525.1); d. Enterococcus faecium NCC 2768 (NCIMB 10415); e. lactobacillus johnsonii NCC 533 (CNCM I-1225) (NCBI refseq; GCA_000008065.1); f. Lactococcus lactis NCC 2287 (CNCM I-4154); g. Lactobacillus paracasei NCC 2461 (CNCM I-2116); h. lactobacillus rhamnosus NCC 4007 (CGMCC 1.3724); i. staphylococcus meat NCC 1052 (CNCM I-5400); j. Staphylococcus sarcodactylis NCC 971 (CNCM I-5398), and/or K. streptococcus thermophilus NCC 2496 (CNCM I-3915); Or a probiotic having a genome with at least 95% Average Nucleotide Identity (ANI), preferably at least 96% ANI, more preferably at least 97% ANI, even more preferably at least 98% ANI, most preferably at least 99% ANI or even 99.5% ANI or 99.9% ANI with any of the genomic sequences of the probiotic according to any of a.to k.as defined above.
3. 3. The composition for use according to claim 2, wherein the probiotic (a) is lactobacillus johnsonii NCC 533 (CNCM I-1225) (NCBI refseq; gca_ 000008065.1) or has a similar activity to lactobacillus johnsonii NCC 533 (CNCM I-1225) (NCBI refseq; GCA 000008065.1,SEQ ID NO:1) has at least 95% ani, preferably at least 96% ani, more preferably at least 97% ani, even more preferably at least 98% ani, most preferably at least 99% ani or even 99.5% ani or 99.9% ani.
4. 4. A composition for use according to any one of claims 1 to 3, wherein the prebiotic (b) is selected from the group consisting of alpha-galacto-oligosaccharides (alpha-GOS)/raffinose, beta-galacto-oligosaccharides (beta-GOS) and Cellooligosaccharides (COS) or combinations thereof.
5. 5. Composition for use according to any one of claims 1 to 4, wherein the prebiotic (b) is selected from soy GOS (α -GOS), pea GOS (α -GOS), cow's milk oligosaccharides (BMOS) (β -GOS), vivinal GOS (β -GOS), cellobiose, cellotriose, cellotetraose and soluble hydrolyzed wheat, human Milk Oligosaccharides (HMO), soluble hydrolyzed oat and/or β -glucan hydrolysates containing cellobiose or cellotriose or cellotetraose or combinations thereof.
6. 6. The composition for use according to any one of claims 1 to 5, wherein the lipid (c) is selected from: a. Triglycerides (TG) consisting of a mixture of butyrates (C4:0) and Medium Chain Fatty Acids (MCFA); b. Triglycerides (TG) consisting of a mixture of short-chain and medium-chain fatty acids (SMCFA), preferably C4 and/or C8 fatty acids; c. Triglycerides (TG) composed of mixtures of butyrates and long chain fatty acids (such as triglycerides composed of mixtures of butyrates and oleates); d. triglycerides composed of medium chain fatty acids; e. triglycerides (TG) composed of short chain fatty acids; f. short chain fatty acids capable of metabolizing to ketone bodies, and G. short-chain fatty acids and medium-chain fatty acids, preferably C4 and/or C8 fatty acids, which are capable of metabolizing to ketone bodies.
7. 7. The composition for use according to any one of claims 1 to 6, wherein: a. The probiotic is selected from at least one of the probiotics according to a.to k.as defined above, or a probiotic having a genome with at least 90% ani, preferably at least 95% ani with any of the genomic sequences of the probiotics according to a.to k.as defined above, or a combination thereof, preferably from lactobacillus johnsonii NCC 533 (CNCM I-1225), or a probiotic having a genome with a sequence of lactobacillus johnsonii NCC 533 (CNCM I-1225) with at least 90% ani, preferably at least 95% ani; b. the prebiotic is selected from the group consisting of alpha-galacto-oligosaccharides/raffinose, beta-galacto-oligosaccharides or cellooligosaccharides or combinations thereof, preferably from the group consisting of soy GOS (alpha-GOS), pea GOS (alpha-GOS), milk oligosaccharides (BMOS) (beta-GOS), vivinal GOS (beta-GOS), cellobiose, cellotriose, cellotetraose, soluble hydrolyzed wheat, soluble hydrolyzed oat and/or beta-glucan hydrolysates containing cellobiose or cellotriose or cellotetraose or combinations thereof; c. The lipid is selected from triglycerides, short chain fatty acids and/or medium chain fatty acids, wherein the triglycerides comprise butyrates, short chain fatty acids, medium chain fatty acids or mixtures thereof, preferably from A. Triglycerides (TG) composed of mixtures of butyrates and Medium Chain Fatty Acids (MCFA); b. Triglycerides (TG) consisting of a mixture of short-chain and medium-chain fatty acids (SMCFA), preferably C4 and/or C8 short-chain and medium-chain fatty acids; c. triglycerides (TG) composed of mixtures of butyrates and long-chain fatty acids (Such as triglycerides composed of a mixture of butyrate and oleate); d. triglycerides composed of medium chain fatty acids; e. triglycerides (TG) composed of short chain fatty acids; f. short chain fatty acids capable of metabolizing to ketone bodies, and G. Short-chain and medium-chain fatty acids, preferably C4 and/or C8 short-chain and medium-chain fatty acids, which are capable of metabolizing to ketone bodies.
8. 8. The composition for use according to claim 7, wherein the probiotic (a) is selected from lactobacillus johnsonii NCC 533 (CNCM I-1225) (NCBI refseq; gca_ 000008065.1) or has a probiotic composition with lactobacillus johnsonii NCC 533 (CNCM I-1225) (NCBIrefseq; GCA_ 000008065.1) a probiotic having a genome with at least 90% ANI, preferably at least 95% ANI.
9. 9. Composition for use according to claim 7 or claim 8, wherein the prebiotic (b) is selected from soy GOS (α -GOS), pea GOS (α -GOS), milk oligosaccharides (BMOS) (β -GOS), vivinal GOS (β -GOS), cellobiose, cellotriose, cellotetraose, soluble hydrolyzed wheat, soluble hydrolyzed oat and/or a β -glucan hydrolysate containing cellobiose or cellotriose or cellotetraose or a combination thereof.
10. 10. The composition for use according to any one of claims 7 to 9, wherein the lipid (c) is selected from: a. Triglycerides (TG) composed of mixtures of butyrates and Medium Chain Fatty Acids (MCFA); b. triglycerides (TG) composed of a mixture of short chain fatty acids and medium chain fatty acids (SMCFA); c. triglycerides (TG) composed of mixtures of butyrates and long chain fatty acids (preferably triglycerides composed of mixtures of butyrates and oleates); d. triglycerides composed of medium chain fatty acids; e. triglycerides (TG) composed of short chain fatty acids; f. short chain fatty acids capable of metabolizing to ketone bodies, and G. Medium chain fatty acids, preferably C4 and/or C8 medium chain fatty acids, capable of metabolizing to ketone bodies.
11. 11. The composition for use according to any one of claims 1 to 10, wherein the probiotic is contained in an amount between 10 3 cfu/daily dose and 10 12 cfu/daily dose, typically in an amount between 10 4 cfu/daily dose and 10 11 cfu/daily dose, preferably in an amount between 10 5 cfu/daily dose and 10 10 cfu/daily dose or in an amount between 10 5 cfu/daily dose and 10 9 cfu/daily dose, also preferably in an amount between 10 6 cfu/daily dose and 10 9 cfu/daily dose, in an amount between 10 6 cfu/daily dose and 10 8 cfu/daily dose or in an amount between 10 8 cfu/daily dose and 10 10 cfu/daily dose, more preferably in an amount between about 10 7 cfu/daily dose and 10 9 cfu/daily dose.
12. 12. The composition for use according to any one of claims 1 to 11, wherein the prebiotic is contained in an amount of 0.1 g/daily dose to 30 g/daily dose, preferably in an amount of between 2 g/daily dose to 15 g/daily dose.
13. 13. The composition for use according to any one of claims 1 to 12, wherein the lipid is contained in an amount of 0.1 g/daily dose to 30 g/daily dose, preferably in an amount of between 2 g/daily dose to 15 g/daily dose.
14. 14. The composition for use according to any one of claims 1 to 13, wherein the lipid is a triglyceride consisting of butyrate and caprylate or a triglyceride consisting of butyrate and oleate.
15. 15. The composition for use according to any one of claims 1 to 13, wherein the lipid is a triglyceride consisting of butyrate and caprylate.
16. 16. The composition for use according to any one of claims 1 to 15 in the form of a food product or nutritional composition, a dietary supplement, a Food for Special Medical Purposes (FSMP), a nutritional supplement, a milk-based beverage, a low volume liquid supplement, a functional food product, a functional beverage product, a meal replacement material, and combinations thereof.
17. 17. The composition for use according to any one of claims 1 to 16, wherein the composition is provided in the form of a powder, a tablet, a capsule, or can be in the form of an oil formulation, an emulsion, an oil-in-water emulsion (o/w emulsion) or a water-in-oil emulsion (w/o emulsion).
18. 18. The composition for use according to any one of claims 1 to 17, wherein said reduction of uremic toxins in cardiovascular metabolic or neurodegenerative disorders is used to delay the progression of such diseases and co-morbidities and/or to manage symptoms and syndromes associated with the toxic effects of uremic solutes of such diseases and co-morbidities.
19. 19. The composition for use according to any one of claims 1 to 18, wherein said reduction of uremic toxins in a condition of vascular metabolism or neurodegeneration comprises: Treatment or prevention of kidney disease, including chronic and acute, dialysis and pre-dialysis, rare diseases, genetically and metabolically induced; treating or preventing uremic syndrome including protein energy expenditure, bone loss, anorexia, fatigue or inflammation; delay of end stage renal disease complications including anemia, hyperphosphatemia, secondary hyperparathyroidism, bone disease, neurological disorders; Delaying the coexistence of kidney disease, including cardiovascular disease; Prevention of risk of malnutrition or management of malnutrition; Delay of progression of cardiovascular metabolic disease; prevention of risk of or management of cardiovascular diseases and comorbidities (diabetes) and/or Prevention of risk of or management of neurodegenerative and neurological disorders.
20. 20. A kit of parts suitable for reducing or avoiding the accumulation of uremic toxins in a cardiovascular metabolic or neurodegenerative disorder, comprising a composition according to any one of claims 1 to 17, comprising the probiotic, the prebiotic and the lipid in two or more separate containers, and optionally further comprising instructions.

Description

Microbiome composition for reducing uremic toxins in cardiovascular metabolic or neurodegenerative disorders The present application claims the benefit of U.S. provisional application No. 63/439,638 filed 18 at 1 month 2023 and U.S. provisional application No. 63/480,729 filed 20 at 1 month 2023, and which includes the sequence listing, the entire disclosures of which are incorporated herein by reference in their entireties. Background The present disclosure relates generally to compositions and methods that allow for reducing or avoiding the accumulation of uremic toxins, preferably in cardiovascular metabolic or neurodegenerative disorders, more preferably in Chronic Kidney Disease (CKD). Such compositions comprise a specifically selected prebiotic, a specifically selected probiotic, and a specifically selected lipid as defined herein. Uremic toxins can generally be divided into three categories, free water-soluble low molecular weight solutes, protein-bound solutes and middle molecules, which are generally products of protein/amino acid metabolism of body tissues, particularly the liver. Uremic toxins include, for example, urea, indoxyl sulfate, TMAO, p-cresol sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, p-tolylglucuronate, and uric acid, among others. The accumulation of such systemic uremic toxins, also known as uremia or uremic status, is a condition commonly observed in individuals with cardiovascular metabolism and neurological disorders including, but not limited to, chronic Kidney Disease (CKD). For example, chronic kidney disease is a disease characterized by progressive and progressive loss of kidney function, and can lead to accumulation of such uremic toxins, which are normally cleared by the kidneys, leading to uremia. Due to the classification of CKD-specific risk factors, CKD patients have an increased risk of developing cardiovascular disease (CVD). Accumulation of uremic toxins in circulation and tissues is associated with the progression of CKD and its complications, including CVD (see Yong Jin Lim et al Toxins 2021,13,142). Chronic Kidney Disease (CKD) and CVD are not the only disorders that show elevated uremic toxin levels, but are also related to other cardiovascular metabolic and neurological disorders. Furthermore, early indicators of excess uremic toxin levels are generally common and are not always clearly attributable to such cardiovascular metabolic and neurological disorders as the primary cause of the first glance. Generally, the accumulation of uremic toxins may lead to symptoms and manifestations including, but not limited to, exhaustion fatigue, anorexia, and protein energy expenditure, which ultimately affect the quality of life of individuals with high levels of circulating uremic toxins. In this case, several publications support the causal role of uremic toxins (including indoxyl sulfate, p-toluol sulfate, TMAO, and urea) in inducing tissue injury and damage (such as kidney or other organs), leading to disease progression and organ failure and death [ ref ：Vanholder R.,Schepers E,Pletinck A,Nagler EV,Glorieux G.2014.J Am Soc Nephrol.25(9):1897-907.doi:10.1681/ASN.2013101062;Falconi et al 2021.Front Physiol.12:686249]. Thus, poor management of systemic uremic toxins can lead to disease progression, the appearance of related symptoms and syndromes (e.g., uremic syndrome, anorexia) and poor quality of life and even patient death. Early intervention is therefore of great importance and necessity in effectively treating such diseases to positively influence the outcome thereof. As indicated generally above, there are generally two main causes that lead to perturbation of uremic toxin levels in the circulation. The first cause is generally increased accumulation due to poor renal filtration. The second is the altered production due to several modifications in metabolism including liver, gut and microbiome. In the prior art, there are several proposals currently available for managing uremic toxins and the causes of uremic toxin level disturbances. Since some uremic toxins may also be from high protein content in the diet, one currently effective solution to manage uremic toxins is to administer a low protein diet to the patient. However, low protein diets are generally not sustainable because patients often require balanced diets and good nutrition. For example, proteins are required to manage other complications associated with kidney disease (e.g., protein energy expenditure). In many cases, low protein diets are even detrimental, for example in cases of anorexia and muscular dystrophy, and in the elderly in general, all of which require a minimum protein content (if not even elevated protein levels) to prevent or treat excessive myoprotein degradation (myocatabolism). Another approach to address uremic toxins, which may be considered the gold standard in renal disease management, is to remove uremic toxins via dialysis. However, this requires continued trea