Metabolome improvement using resistant starch supplementation

Abstract

Resistant potato starch (RPS) is a form of dietary fiber that has been evaluated for improving insulin sensitivity and promoting the growth of bifidobacteria in the gut. When RPS is administered in human trials, unexpected beneficial changes occur in the abundance of several metabolites related to memory and cognitive function, bile acid metabolism, immune function, collagen metabolism, polyamine levels, mitochondrial function, oxidative stress, exercise capacity and male health, and fatty acid hydroxylation. The diverse categories of metabolites affected by RPS have revealed many underestimated benefits obtained by consuming this form of dietary fiber.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,194, filed on July 4, 2022, entitled "METABOLOMIC IMPROVEMENTS USING RESISTANT STARCH SUPPLEMENTATION", the entire content of which is incorporated herein by reference for all purposes.

Background Art

[0002] Resistant starch (RS) is "the sum total of all starch and starch degradation products that, on average, reach the human large intestine" [1]. Thus, RS is a form of dietary fiber and is recognized by regulatory authorities (e.g., https: / / www.canada.ca / en / health - canada / services / publications / food - nutrition / list - reviewed - accepted - dietary - fibres.html). The levels of RS in foods habitually consumed by Americans are low [2], in contrast to the historical diet that included more than 20 g of RS per day [3]. Experts have suggested that it is necessary to restore the dietary intake of RS to at least 15 g per day in order to improve gastrointestinal health and promote insulin sensitivity [2]. However, the relationship between RS and broader aspects of human health has not been studied heretofore.

[0003] The "metabolome" refers to "the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids" [4]. It is considered that "the metabolic state of a human represents something close to the overall health state of that individual", and this metabolic state is thought to reflect the external influences including the human genome, diet, environmental factors, and gut microbiota [4]. Changes in metabolites can potentially affect human physiology by promoting or inhibiting various cellular activities and biochemical processes, leading to an investigation of dietary inputs that can actively improve human health through individual metabolome changes or changes that affect the entire set of metabolites.

[0004] The supply of RS, or the consumption of foods rich in RS, is associated with an increase in microbe-derived metabolites called short-chain fatty acids (SCFAs), particularly butyric acid [5]. We previously discovered a significant increase in the abundance of butyric acid in the fecal samples of elderly individuals who consumed 30 g of resistant potato starch (RPS) per day [6]. Butyric acid is beneficial to many aspects of cell and host health, such as cancer prevention and the promotion of normal epithelial cell function [7]. Some of these benefits are related to the local activity of butyric acid in the large intestine, but the systemic effects associated with butyric acid represent butyric acid that is produced in the intestine but not absorbed by colon cells or the host, with a low correlation with fecal butyric acid levels. The supplementation of butyric acid is not beneficial to patients with metabolic syndrome, which is thought to be attributed to the rapid clearance and low availability of systemic butyrate [8].

[0005] In this study, the inventors attempted to evaluate the effect of RS on serum SCFA levels by measuring the effects of different doses and administration periods in two clinical trials. Furthermore, the inventors measured other short-chain organic acids, medium-chain fatty acids, long-chain fatty acids, amines and amino acids, carnitine, and bile acids in these serum samples using a targeted panel assay. Surprisingly, the inventors found that RPS had no significant effect on butyric acid and other SCFAs in the serum. However, the inventors detected significant changes in the serum levels of several different metabolites, suggesting that RPS supplementation may affect host physiology in more ways than previously known.

SUMMARY OF THE INVENTION

[0006] According to one aspect of the present invention, there is provided a method of modifying the level of a microbially influenced metabolite in human serum produced by the fermentation of resistant potato starch in the human intestine, the method comprising administering to the human an effective amount of a suitable resistant potato starch based on an administration regimen.

[0007] According to one aspect of the present invention, there is provided a method of increasing the circulating level of the neurosteroid pregnenolone sulfate in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0008] In another aspect of the present invention, there is provided a method of increasing the circulating level of 3-β-hydroxy-5-cholestenic acid in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0009] In another aspect of the invention, there is provided a method of causing a decrease in the circulating levels of glycine and / or taurine conjugated bile acids in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0010] In another aspect of the invention, there is provided a method of causing a decrease in the circulating levels of bile acids in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0011] In another aspect of the invention, there is provided a method of causing a decrease in the bacterial bile salt hydrolase activity in the intestine of an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0012] In another aspect of the invention, there is provided a method of causing a decrease in the circulating levels of 3-hydroxykynurenine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0013] In another aspect of the invention, there is provided a method of causing a decrease in the circulating levels of the amine histamine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0014] In another aspect of the invention, there is provided a method of causing a decrease in the circulating levels of the collagen degradation product 5-hydroxylysine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0015] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of the collagen degradation product 4-hydroxyproline in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0016] In another aspect of the invention, there is provided a method of preventing the degradation of collagen in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0017] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of the polyamine N-acetylputrescine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0018] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of the polyamine N-acetylspermidine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0019] In another aspect of the invention, there is provided a method of enhancing the circulating level of polyamines in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0020] In another aspect of the invention, there is provided a method of causing an increase in the circulating acylcarnitine level in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0021] In another aspect of the invention, a method of causing a decrease in the ratio of circulating short-chain and medium-chain carnitine to free carnitine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen, is provided.

[0022] In another aspect of the invention, a method of enhancing mitochondrial β-oxidation in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen, is provided.

[0023] In another aspect of the invention, a method of causing an increase in the circulating level of propionylcarnitine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen, is provided.

[0024] In another aspect of the invention, a method of causing an increase in the circulating level of serotonin in an individual in need of such treatment by decreasing the 5-hydroxyindoleacetic acid to serotonin ratio, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen, is provided.

[0025] In another aspect of the invention, a method of causing an increase in the circulating level of coenzyme Q10 in an individual in need of such treatment by increasing the coenzyme Q10 to phenylalanine ratio, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen, is provided.

[0026] In another aspect of the invention, a method of enhancing mitochondrial function in an individual in need of such treatment by decreasing the circulating short-chain to free carnitine ratio or increasing the coenzyme Q10 to phenylalanine ratio, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on an administration regimen, is provided.

[0027] According to another aspect of the invention, a method of causing a decrease in the circulating level of hydroxydecanoic acid in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on an administration regimen, is provided.

[0028] In some embodiments of the invention, the administration regimen is to administer the resistant potato starch daily over a period of 1 to 12 weeks. In this context, "daily" does not necessarily mean "everyday", and can mean, for example, 19 out of 20 days, 9 out of 10 days, 17 out of 20 days, 8 out of 10 days.

[0029] As discussed herein, the effective amount can be, for example, 0.5 to 40 g, or 0.5 to 30 g, or 0.5 to 7 g, or 0.5 to 3.5 g of resistant starch.

Brief Description of the Drawings

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BEST MODE FOR CARRYING OUT THE INVENTION

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference.

[0032] As used herein, "treating" does not necessarily require "curing" of a disease, disorder, episode, occurrence, or incident in all its grammatical forms, but rather refers to at least one of reducing the frequency, and / or duration, and / or severity of the affection of the disease and / or one or more symptoms associated with the disease, disorder, episode, occurrence, or incident.

[0033] As used herein, "circulation level" refers to the level of the compound(s) circulating in the blood of a patient or subject. Preferably, the patient or subject is a human.

[0034] The inventors investigated the effect of resistant potato starch (Solnul™) in two separate clinical trials. MSP Starch Products Inc manufactures Solnul™, a food-grade high-quality potato starch of the RS type 2 for human and animal food applications. Solnul™ containing 60% RS (by AOAC method 2002.02) was used in the tests and experiments discussed herein, but as discussed herein, another suitable native potato starch or resistant potato starch (RS type 2) containing at least 50% resistant starch, or at least 55% resistant starch, or at least 60% resistant starch on an "as is" basis and meeting the USP standards of potato starch can be used. It is important to note this.

[0035] As discussed herein, the inventors have demonstrated that the replenishment of resistant potato starch (RPS) modulates several metabolite levels in serum. Specifically, RPS increased serotonin by decreasing the levels of the 5-hydroxyindoleacetic acid to serotonin ratio, the neurosteroid pregnenolone sulfate and the gamma-secretase inhibitor 3-β-hydroxy-5-cholestenic acid, and the carnitines propionylcarnitine and heptanoylcarnitine, and increased coenzyme Q10 by increasing the coenzyme Q10 to phenylalanine ratio.

[0036] Furthermore, RPS decreased the serum levels of bile acids, including those conjugated to glycine and taurine, the collagen degradation products 4-hydroxyproline and 5-hydroxylysine, the inflammation-related amine histamine, the polyamines N-acetylputrescine and N-acetylspermidine, the ratio of short-chain and medium-chain carnitines to free carnitine, the neurotoxic metabolite 3-hydroxykynurenine, and hydroxydodecanoic acid.

[0037] The initial clinical trial was a prospective randomized double-blind placebo-controlled study conducted from April 2019 to October 2019 in Winnipeg, Manitoba, Canada by Source Nutraceutical (Winnipeg, MB) and Cliantha Research (formerly Hill Top Research Ahmedabad, GJ, India). Since the study was designed to replicate a previous clinical trial [9], no formal power analysis was performed [6]. Participants were divided into subgroups by age (30 - 50 years: MID, or over 70 years: ELD) and then assigned to either the placebo group or the study product group based on a randomized list created by Karmic Life Sciences (Mumbai, MH, India). The trial participants, the principal investigator, the outcome assessors, and the data analysts were blinded to which treatment the participants were assigned. All information collected for the purposes of the study was stored in a secure locked location. All information collected and sent for statistical analysis had only the study number and no identifying information for the participants. All information identifying the participants was handled confidentially in accordance with the Personal Health Information Act of Manitoba.

[0038] This study was explained verbally and in writing to eligible participants, and all participants provided written informed consent. Participants were informed that they could request to withdraw from the clinical study at any time without adverse effects. Exclusion criteria included the following. Pregnancy, planned pregnancy, or lactation during the study period, Crohn's disease or other inflammatory bowel diseases, individuals with systemic lupus erythematosus or during cancer chemotherapy, individuals with prediabetes or diabetes, thyroid diseases, kidney diseases, liver diseases, individuals with a history of gastrointestinal surgery (bowel resection, gastric bypass, colorectal surgery), individuals taking probiotics (including potential probiotic foods such as yogurt), individuals taking antibiotics at the time of recruitment, or individuals who had taken antibiotics within the past five weeks, individuals experiencing dysphagia, subjects using additional dietary fiber supplements, subjects allergic to potatoes or corn, and individuals taking digestive drugs, emetics, antiemetics, drugs for the treatment of acid peptic diseases, and antacids. Female participants underwent a pregnancy test at each visit to confirm that they were not pregnant. Except for the requirement not to take probiotic products, there were no changes to the participants' normal diets that they consumed daily. Participants were screened to determine eligibility according to the above inclusion / exclusion criteria, and blood samples were screened for abnormalities in urea, creatinine, aspartate transaminase, alanine transaminase, alkaline phosphatase, and creatine kinase (Dynacare, Brampton, ON). After screening, a qualified principal investigator confirmed the subject's health information and enrolled them in the study.

[0039] All eligible trial participants were enrolled during a 2-week run-in period, during which they took 30 g of placebo once daily to acclimatize all subjects to supplement intake. Subjects were recommended to mix the product into 250 mL of non-heated liquid or non-heated semi-solid food and, for those taking medications, to take the product 2 hours before or 2 hours after taking the medication. At all study visits, subjects had their height, weight, body mass index (BMI), waist circumference, and hip circumference measured and their blood pressure checked. After the run-in period, subjects were randomly assigned to groups that received RPS or a placebo of fully digestible corn starch (each individually packaged in an amount of 30 g) at 30 g per day for 12 weeks.

[0040] Daily records of antibiotic use, hospitalizations, and clinic visits were collected. At baseline and at the end of the 12-week intervention, fasting serum samples were collected and stored at -80 °C (MRM Proteomics, Montreal, QC) prior to mass spectrometry (The Metabolomics Innovation Centre / The UVic-Genome BC Proteomics Centre, Victoria, BC). Overall, data from a total of 81 participants were analyzed, 44 who received RPS (20 MID and 24 ELD) and 37 who received placebo (15 MID and 22 ELD) (Figures 1 and 2).

[0041] In the second clinical trial, the participants were generally healthy adult men and women between 18 and 69 years of age, with a body mass index (BMI) of 18.0 - 34.9 kg / m 2 as follows. Enrolled participants agreed not to use new vitamins, minerals, and dietary supplements until after study completion and, because intake of vitamins, minerals, and dietary supplements could bias the results of the test product, not to take these products from 14 days before the second visit (randomization) until after completion of the fourth visit. For those with a BMI of 34.9 kg / m 2Individuals over were excluded because their health status and related metabolic changes might affect the results of this study. For similar health reasons, all individuals diagnosed with irritable bowel syndrome, indigestion, severe gastrointestinal disorders, or other major diseases were excluded. A formal sample size calculation was not performed. The sample size of 25 subjects per study group is consistent with our previous clinical investigations of RS [9][6].

[0042] To obtain the required sample size of 75 participants (25 per study group) enrolled in the pilot study conducted from October 20, 2019, to January 6, 2020, a total of 98 participants from Guelph, Ontario, and its surrounding areas were screened for eligibility. The identity regarding the study intervention was blinded to the study staff and participants. In this study, screening visits from 30 days to 14 days before randomization, a run-in period from 14 days to 17 days before randomization, a baseline visit (day 0) where randomization was performed and serum was collected, and two subsequent study visits where serum was collected at week 1 and week 4 were conducted respectively.

[0043] At baseline (day 0) of the visit, participants were randomized into one of three study interventions (high dose (7 g of resistant potato starch (RPS)), low dose (combination of 3.5 g of RPS and 3.5 g of digestible corn starch), or placebo (7 g of digestible corn starch)) indicated by a randomization scheme. The randomization scheme was created by Nutrasource at 19:15:44:40 on October 22 using SAS 9.4 PROC PLAN with a seed number of 1887363180. Seventy-five subjects were randomly assigned to 25 blocks, with 3 subjects in each block. The initial dose of the study intervention was administered by mixing the product in approximately 125 mL of cold or room-temperature water and drinking it immediately before the study drug precipitated. Participants were instructed to take the study drug in the morning. Study participants were provided with 31 days' worth of the study intervention at the baseline visit. At the third visit (week 1), unused study intervention / empty packages were collected and compliance was calculated. At the fourth visit (week 4, final study visit), unused study products / empty packages were collected and compliance was calculated.

[0044] Participants were instructed to return all sachets given at the third and fourth visits and not to discard opened or unopened sachets. Compliance was calculated based on the amount of study product ingested compared to the total amount of study product expected to be ingested over a given period. Compliance for this study was considered satisfactory if participants ingested on average 80% or more of the study product over a given period. One participant per treatment group discontinued the study prior to the fourth visit, and two participants in the high-dose RPS group were excluded due to non-compliance (<80% product ingestion) and use of a prohibited study medication. The safety profile was based on the safety analysis set (SAF; n = 75), the full analysis set (FAS; n = 72) included participants who received at least one dose of the study product and had at least one outcome assessment after dosing, and the per-protocol population (PP; n = 70) included only participants who completed the study while generally adhering to the study parameters. Serum samples were stored at -80°C prior to mass spectrometry (The Metabolomics Innovation Centre / The UVic-Genome BC Proteomics Centre, Victoria, BC) (MRM Proteomics, Montreal, QC).

[0045] Mass spectrometry of metabolites in serum was performed by The Metabolomics Innovation Centre (Victoria, BC). UPLC-MRM / MS was performed by coupling an Agilent 1290 UHPLC (Agilent Technologies, Santa Clara, CA) to a Sciex 4000 QTRAP mass spectrometer (AB Sciex, Framingham, MA) and operating in the multiple reaction monitoring mode for negative ion detection. The internal standard solution was prepared in MeOH-acetonitrile and serially diluted with water. Serum samples were thawed at room temperature, aliquots were mixed with the internal standard solution, vortexed, and sonicated in a water bath prior to centrifugation for clarification. Aliquots of the supernatant were mixed with water to prepare the sample solution. Also, a pooled sample of 10 randomly extracted aliquots was prepared as a QC sample solution and injected every 20 samples. UPLC-MRM / MS data were acquired with Sciex Analyst software and batch processed with Sciex MultiQuant software (AB Sciex). Linear calibration curves for metabolites were generated using the standard solution concentration of each analyte in an appropriate concentration range versus the analyte-to-internal standard peak area ratio. The concentration detected in each sample was calculated by interpolating the calibration curve with the analyte-to-internal standard substance peak area ratio measured from each sample.

[0046] Baseline values of metabolites were compared using Student's t-test against 1 week, 4 weeks (Study 2), or 12 weeks (Study 1), and a p-value < 0.05 was considered significant in any study only if the t-test against the change in the placebo group did not yield a p-value < 0.05 in the same direction as the RPS treatment (i.e., if placebo treatment also did not result in a significant effect on metabolites).

[0047] RPS significantly increased pregnenolone sulfate (A in Figure 1), a neurosteroid, and 3-β-hydroxy-5-cholestenic acid (B in Figure 1), a gamma-secretase inhibitor, at both 3.5 g and 7 g daily doses. RPS supplementation significantly decreased glycol-α-muricholic acid (A in Figure 2) and glycohyocholic acid (B in Figure 2), glycine-conjugated bile acids, at 3.5 g per day, and 30 g / day of RPS significantly decreased glycol-α-muricholic acid (B in Figure 2) in the pooled cohort and significantly decreased glycohyocholic acid (D in Figure 2) and glycoursodeoxycholic acid (E in Figure 2) in the ELD cohort. Similarly, RPS supplementation significantly decreased taurocholic acid (A in Figure 3), tauro-ω-muricholic acid (B in Figure 3), tauroursodeoxycholic acid (C in Figure 3), and taurochenodeoxycholic acid (E in Figure 3), taurine-conjugated bile acids, at 3.5 g per day. At 30 g / day, RPS significantly decreased tauroursodeoxycholic acid in the ELD cohort (D in Figure 3) and significantly decreased taurochenodeoxycholic acid 3-sulfate in the pooled cohort (F in Figure 3). Comparing the ratios of sugar- and taurine-conjugated primary and secondary bile acids to unconjugated primary and secondary bile acids demonstrated a significant decrease in the 3.5 g / day dosing group compared to the placebo group (G in Figure 3). The 30 g / day dose also significantly decreased muricholic acid (A in Figure 4) and ursodeoxycholic acid 3-glucuronide (B in Figure 4) in the pooled cohort.

[0048] Participants who ingested 3.5 g of RPS per day experienced a significant decrease in 5-hydroxylysine (A in Figure 5), histamine (B in Figure 5), and 4-hydroxyproline (C in Figure 5). Polyamine metabolism was affected at all doses of RPS. N-acetylputrescine significantly decreased at 3.5 g (A in Figure 6) and at 30 g in the ELD cohort (B in Figure 6). N-acetylspermidine significantly decreased at 3.5 g and 7 g doses (C in Figure 6) and significantly decreased at 30 g in the middle-aged and older (MID) and pooled cohorts (D in Figure 6).

[0049] The metabolism of acylcarnitine was significantly affected by a 30 g dose of RPS. Propionylcarnitine increased in the MID and pooled populations (Figure 7A), while heptanoylcarnitine increased in the pooled population (Figure 7B). Hydroxydecanoic acid significantly decreased in healthy adults at a 7 g dose (Figure 8A) and in the ELD at a 30 g dose (Figure 8B).

[0050] Serotonin levels were nominally higher without significant differences at all three doses (Figure 9A), there was no significant difference in the serotonin-to-tryptophan ratio (Figure 9B), but the 5-hydroxyindoleacetic acid-to-serotonin ratio was significantly affected by the treatment (Figure 9C).

[0051] The concentration of coenzyme Q10 increased significantly in response to both a 3.5 g administration and placebo (Figure 10A). Coenzyme Q10 is synthesized from several other molecules such as the amino acids tyrosine and phenylalanine (Figure 10B). Tyrosine levels (Figure 10C) and phenylalanine levels (Figure 10D) significantly decreased in the 3.5 g RPS group. The coenzyme Q10-to-tyrosine ratio showed a significant trend (Figure 10E), but the coenzyme Q10-to-phenylalanine ratio was significantly greater in participants who received a 3.5 g administration (Figure 10F).

[0052] The ratio of short-chain and medium-chain carnitine to free carnitine significantly decreased in the 3.5 g administration group compared to placebo (Figure 11A), but the ratio of long-chain carnitine to free carnitine (Figure 11B) and the level of dicarboxyl carnitine (Figure 11C) were not affected by the treatment.

[0053] Finally, participants who received placebo experienced an increase in kynurenine (Figure 12A), while participants who ingested 3.5 g of RPS per day experienced a decrease in 3-hydroxykynurenine (Figure 12B). The 3-hydroxykynurenine-to-kynurenine ratio was not affected by the treatment (Figure 12C).

[0054] Pregnenolone sulfate and 3-β-hydroxy-5-cholestenic acid are both cholesterol-derived metabolites that affect neuronal function [10, 11]. Pregnenolone sulfate is a nootropic and a modulator of neurotransmission, playing a role in learning and memory

[11] . Serum pregnenolone sulfate levels in women with menstrual-related migraine are significantly lower (mean 39.58 ng / mL) compared to the control group (mean 55.82 ng / mL)

[12] , and in schizophrenic patients treated with pregnenolone, baseline serum pregnenolone sulfate levels are inversely correlated with MATRICS Consensus Cognitive Battery scores

[13] , indicating that increasing serum levels of pregnenolone sulfate may have therapeutic benefits. 3-β-hydroxy-5-cholestenic acid is normally found in the blood at 67.2 + / - 27.9 ng / mL (mean + / - SD)

[14] , and its levels are decreased in patients with ileal resection

[15] . 3-β-hydroxy-5-cholestenic acid is a selective gamma-secretase modulator that acts specifically on amyloid-beta 42 (Aβ42), reducing the Aβ42 to Aβ38 ratio, suggesting that increasing 3-β-hydroxy-5-cholestenic acid may be beneficial in reducing Alzheimer's disease

[10] . Resistant starch has not been previously associated with changes in any of these metabolites. Bile acids are produced from cholesterol by the liver, secreted from the gallbladder, emulsify dietary fats, and facilitate the absorption of lipids and fat-soluble nutrients. Resistant corn starch decreases the excretion of bile acids in feces [16, 17], reduces total bile acids and secondary bile acids

[18] , does not affect primary bile acids [19, 20], and increases bile acid excretion [21, 22, 23]. RS from adzuki and kidney beans, and all RS from potatoes, promoted bile acid excretion in feces [24, 25, 26, 27]. RS has previously been shown to have different effects on taurochenodeoxycholate [22, 28], and RS from lotus seeds has been shown to convert taurocholic acid to taurodeoxycholic acid without affecting taurine conjugation itself

[29] .From the above results, the inventors' findings are that, for the first time, RPS is shown to constantly reduce the serum abundance of taurine- and glycine-conjugated bile acids and the abundance of muricholic acid and ursodeoxycholic acid 3-glucuronide by potentially enhancing the bile acid hydrolase activity of the gut microbiota.

[0055] The amounts of 5-hydroxylysine and 4-hydroxyproline in serum and urine are markers of collagen breakdown, and increased levels thereof are characteristic of several diseases including diabetic nephropathy

[30] , viral hepatitis

[31] , progressive osseous heteroplasia

[32] , Paget's disease

[33] , chronic bronchitis, pneumonia, emphysema

[34] , decompensated cirrhosis

[35] , mucopolysaccharidosis, and irritable bowel syndrome

[36]

[37] . The serum levels of this metabolite increase after exercise

[38]

[39]

[40] , and skeletal muscle collagen is broken down during muscle fiber remodeling. The inhibition of RPS-dependent collagen breakdown may be due to the reduction of inflammation by the decrease in histamine levels, since collagenase activity is closely related to neutrophil migration in response to histamine

[41] , or it may be due to the improvement of mitochondrial function and the decrease in the production of reactive oxygen species, which are known to increase collagenase activity

[42] . To the best of the inventors' knowledge, this is the first report associating the intake of RPS with a decrease in serum 5-hydroxylysine or 4-hydroxyproline or the promotion of collagen integrity.

[0056] Histamine, which is an amine, is released by mast cells at the local site of inflammation, where it acts as a vasodilator and promotes the immune response

[43] . In individuals with chronic urticaria

[44] , histamine intolerance, atopic eczema

[45] , food allergy, major depressive disorder

[46] , and idiopathic anaphylaxis

[47] , histamine levels are increased. The normal basal plasma histamine level ranges from 2.7 to 9.0 nM, and in patients exceeding 9 nM, symptoms of HIT such as increased gastric acid secretion and increased heart rate have been reported

[48] . Histamine also plays a role as a neurotransmitter, and when RS is supplemented to rats fed a high-fat diet, the histamine receptor insensitivity caused by the high-fat diet is reversed

[49] . However, the role of RS in the modulation of histamine levels has not been reported so far.

[0057] Putrescine and spermidine are both polyamines that are produced in a step following the decarboxylation of ornithine. Polyamines play an important role in cell proliferation, as indicated by the increased polyamine levels in proliferating cancer cells

[50] . Polyamine levels are negatively regulated via acetylation and are normally found in the serum of healthy individuals

[51] , and enhancing the enzymes involved in polyamine acetylation has been a pharmacological strategy used in the development of chemotherapy

[52] . Notably, higher N-acetylspermidine levels have been associated with poor outcomes in patients with COVID-19

[53]

[54]

[55] , and high levels of this metabolite have been associated with cardiovascular disease

[56] , and various cancers including hepatocellular carcinoma

[57] , colorectal cancer

[58] , glioblastoma

[59] , and breast cancer

[60] . To the best of the inventors' knowledge, the inventors are the first to describe the relationship between the intake of RS and the decrease in N-acetylputrescine or the decrease in N-acetylspermidine. Acylcarnitine is carnitine esterified to a fatty acid via acyl coenzyme A and has historically been measured in cases of inborn errors of fatty acid oxidation, although short-chain acylcarnitines have recently been approved by the Food and Drug Administration for nutraceutical purposes

[61] . In obese women with polycystic ovary syndrome, endogenous propionylcarnitine levels significantly increase in response to pioglitazone, which is associated with improved fatty acid metabolism and improved mitochondrial function

[62] . Supplementation with propionylcarnitine promotes heart and vascular health, mitochondrial function, lipid peroxidation, and erectile function

[63]

[64]

[65]

[66]

[67]

[68]

[69] . There is also evidence supporting the role of propionylcarnitine in exercise performance

[65]

[70] . Resistant starch (RS type 4) chemically modified via a propionate conjugate has been shown to increase propionylcarnitine in cats, but since acetylated resistant starch did not increase propionylcarnitine, these effects were due to the propionyl moiety

[71] .Our data are the first to demonstrate that native RPS (RS type 2) significantly increases propionylcarnitine and heptanoyl carnitine.

[0058] Serotonin is a monoamine neurotransmitter derived from the essential amino acid tryptophan and plays an important role in various physiological aspects, including anxiety and stress responses

[72] . Serotonin levels can be decreased by a dietary deficiency of tryptophan, and maintaining sufficient serotonin levels continues to be a major therapeutic approach for individuals with clinical depression

[73] . Serotonin is degraded to 5-hydroxyindoleacetic acid via monoamine oxidase (MAO)

[74] , and MAO inhibitors are pharmacological agents used to treat neurological symptoms such as depression by increasing serotonin levels

[75] . Our data are the first to demonstrate that native RPS (RS type 2) significantly decreases the 5-hydroxyindoleacetic acid to serotonin ratio potentially through microbial-derived metabolites from intestinal RPS fermentation that affect MAO activity.

[0059] Coenzyme Q10 is an antioxidant that endogenously synthesizes in a complex manner either by generating 4-hydroxybenzoic acid from tyrosine or phenylalanine and then generating benzoquinone, or by generating a polyisoprenyl side chain from acetyl-CoA via the mevalonic acid pathway and then condensing the benzoquinone and the polyisoprenyl side chain

[76] . Coenzyme Q10 functions as an electron carrier within mitochondria during oxidative phosphorylation, plays an important role as a lipid-soluble antioxidant, and protects both mitochondria and other cell membranes from free radical-induced oxidative stress

[76] . The tissue level of coenzyme Q10 correlates with oxidative function, and its level is highest in the heart, kidney, liver, and muscle, further supporting the physiological protective state of this substance

[77] . Administration of RPS increased the serum coenzyme Q10 level by 0.4 mg / mL, which corresponds to a level of more than 40% after 4 weeks. The coenzyme Q10 level increased significantly over time in both the RPS group and the placebo group, but the ratio of coenzyme Q10 to phenylalanine was significantly greater in the RPS group, indicating that RPS promotes the synthesis of coenzyme Q10. Given that the administration of RPS also promotes β-oxidation, the promotion of coenzyme Q10 synthesis may reflect an overall improvement in mitochondrial function in response to RPS supplementation.

[0060] In addition to supplementing carnitine to support mitochondrial function, the ratio of acylcarnitine to free carnitine can be beneficial depending on its length. The short-chain and medium-chain acylcarnitine-to-free carnitine ratios tend to accumulate in cases of mitochondrial dysfunction, leading to a relative accumulation of shorter acylcarnitines when the catabolism of acyl chains by β-oxidation is poor

[78] . Surprisingly, the inventors have observed a decrease in the short-chain and medium-chain acylcarnitine-to-free carnitine ratios, which further demonstrates that RPS promotes mitochondrial function and β-oxidation. This change in the ratio may reflect the promotion of the utilization of microbe-derived metabolites generated by intestinal RPS fermentation in mitochondria.

[0061] Tryptophan is a precursor for serotonin production, but most tryptophan is metabolized to kynurenine

[79] . Kynurenine is further metabolized to 3-hydroxykynurenine, which is a substance with cytotoxic and neurotoxic activities due to the generation of reactive oxygen species

[80] . In patients with Alzheimer's disease

[81] and model mice with Huntington's disease

[82] , the level of 3-hydroxykynurenine has increased, and interventions to reduce the level of 3-hydroxykynurenine are being explored

[83] . As far as the inventors know, the relationship between the supply of resistant starch and the decrease in 3-hydroxykynurenine is not known. The decrease in 3-hydroxykynurenine may be secondary to the decrease in 5-hydroxyindoleacetic acid dependent on RPS, or may act in parallel, reflecting the intestinal-derived effects on serotonin metabolism.

[0062] Hydroxydecanoic acid is a general term for all forms of decanoic acid hydroxylated at various carbon positions, such as those contained in royal jelly and those used to artificially modify the mitochondrial potassium ATP channel

[84]

[85] . The role of hydroxydecanoic acid in health is not well defined, but our data are the first to show that the supply of RPS significantly reduces the amount of this metabolite. As discussed herein and summarized above, the supply of RPS significantly changed the metabolome profiles of several metabolites related to health promotion. However, changes in short-chain fatty acids typically associated with RPS supply, such as butyrate, were not detected. RS is a historically abundant and important form of dietary fiber in the human diet [2], and it is thought that human physiology has evolved to depend on dietary sources of RS to supply sufficient nutrients and upregulate the levels of biologically relevant metabolites.

[0063] Although not wishing to be bound by any particular theory or hypothesis, supplementation with RPS, an indigestible form of dietary fiber, may affect digestive enzyme activity and / or alter nutrient absorption in the gut, resulting in changes to the host metabolome. Additionally, supplying RS to the gut microbiota may result in changes to the bacterial-derived metabolites, and changes in the host metabolomics may be due directly to changes in the absorption of these metabolites from the gut microbiota or indirectly due to the host's response to the metabolites produced by the microbiota. That is, these host metabolites are under microbial influence in that changes to the gut microbiota affect the levels of these host metabolites as discussed herein.

[0064] In summary, contrary to what was predicted from the literature, the inventors were unable to detect significant changes in serum SCFAs, including no change to butyrate, the final product of RPS fermentation. Instead, the inventors found that supplementation with RPS positively affected the abundance of many metabolites that have not previously been associated with RS fermentation by the gut microbiota, across a range of doses and durations. Further research is needed to elucidate the mechanisms by which the above metabolite changes may be attributable to RPS ingestion.

[0065] According to one aspect of the invention, there is provided a method of modifying the levels of microbially-influenced metabolites in human serum produced by the fermentation of resistant potato starch in the human gut, the method comprising administering to the human an effective amount of resistant potato starch suitable based on an administration regimen.

[0066] In some embodiments, the microbially-influenced metabolites are collagen, collagen breakdown products, short-chain organic acids, medium-chain fatty acids, short-chain fatty acids, amines, amino acids, carnitine, or bile acids.

[0067] In some embodiments, the metabolites affected by the microorganism are selected from the group consisting of collagen, 5-hydroxylysine, 4-hydroxyproline, pregnenolone sulfate, 3-β-hydroxy-5-cholestenic acid, 3-hydroxykynurenine, histamine, N-acetylputrescine, N-acetylspermidine, acylcarnitine, carnitine, propionylcarnitine, serotonin, coenzyme Q10, and hydroxydodecanoic acid.

[0068] According to one aspect of the invention, there is provided a method of increasing circulating neurosteroid pregnenolone sulfate levels in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0069] Thus, in this context, an "individual in need of such treatment" is an individual having circulating serum pregnenolone sulfate levels lower than those of a control individual, e.g., lower than 56 ng / mL, or lower than 40 ng / mL, or an individual suffering from frequent migraine headaches, e.g., menstrual-related migraines or headaches, or having a neurocognitive disorder, e.g., a cognitive disorder, schizophrenia, or other neurological disease, or an individual such as a student, studying, or otherwise in need of enhanced memory function.

[0070] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for increasing circulating serum pregnenolone sulfate levels or for reducing the severity and / or frequency of migraine headaches as compared to individuals of similar age and condition not receiving an administration regimen (referred to elsewhere herein as "control individuals").

[0071] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for treating frequent migraine headaches, e.g., menstrual-related migraines or headaches.

[0072] According to another aspect of the invention, the use of native RPS (RS type 2) for treating neurocognitive disorders, such as cognitive impairment, schizophrenia, or other neurological conditions, is provided.

[0073] According to another aspect of the invention, the use of native RPS (RS type 2) for enhancing memory function when an individual is studying or is a student is provided.

[0074] In another aspect of the invention, a method of increasing the circulating level of 3-β-hydroxy-5-cholestenic acid in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen, is provided.

[0075] Thus, in this context, an "individual in need of such treatment" can be an individual in whom the circulating 3-β-hydroxy-5-cholestenic acid is lower than in a control individual, e.g., an individual having 67.2 ng / mL or less, or 67 ng / mL or less, or an individual suffering from Alzheimer's disease or having a genetic risk of developing Alzheimer's disease, or an individual in need of a modulator of gamma-secretase activity.

[0076] According to another aspect of the invention, the use of native RPS (RS type 2) for increasing circulating 3-β-hydroxy-5-cholestenic acid is provided.

[0077] According to another aspect of the invention, the use of native RPS (RS type 2) for treating or reducing the severity of symptoms associated with Alzheimer's disease is provided.

[0078] In another aspect of the invention, a method of reducing the circulating level of glycine-conjugated bile acids and / or taurine-conjugated bile acids in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen, is provided.

[0079] Thus, in this context, "an individual in need of such treatment" can be an individual having increased circulating serum levels of taurine-conjugated bile acids and glycine-conjugated bile acids compared to a control individual.

[0080] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for reducing the circulating serum levels of taurine-conjugated bile acids and glycine-conjugated bile acids.

[0081] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for treating dyslipidemia, hypercholesterolemia, obesity, metabolic syndrome, diabetes, or related metabolic disorders.

[0082] In another aspect of the invention, there is provided a method of enhancing probiotic activity in an individual in need of such treatment, the method comprising administering to the individual an effective amount of resistant potato starch based on a dosing regimen.

[0083] Thus, in this context, "an individual in need of such treatment" can be an individual who is also ingesting probiotics, either in a formulation containing RPS or in another form not containing RPS.

[0084] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for supporting the survival or viability of probiotics.

[0085] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for treating antibiotic-associated diarrhea, idiopathic diarrhea, constipation, or other forms of gastrointestinal distress.

[0086] In another aspect of the present invention, there is provided a method of causing a reduction in the circulating levels of bile acids in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen.

[0087] Alternatively, an "individual in need of such treatment" can be an individual having increased circulating levels of bile acids compared to a control individual and / or an individual having or at risk of developing dyslipidemia, hypercholesterolemia, obesity, metabolic syndrome, diabetes, or a related metabolic disorder.

[0088] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for reducing the circulating levels of bile acids.

[0089] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for treating dyslipidemia, hypercholesterolemia, obesity, metabolic syndrome, diabetes, or a related metabolic disorder.

[0090] In another aspect of the present invention, there is provided a method of causing a reduction in the circulating levels of the tryptophan metabolite 3-hydroxykynurenine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen.

[0091] Thus, in this context, an "individual in need of such treatment" can be an individual having increased circulating levels of 3-hydroxykynurenine compared to a control individual, e.g., an individual having a baseline urinary 3-hydroxykynurenine level above 450 μg / g creatinine, or an individual suffering from or predisposed to Alzheimer's disease, Huntington's disease, Parkinson's disease, vitamin B6 deficiency, or an individual receiving hydrocortisone treatment or an individual who is pregnant.

[0092] In another aspect of the invention, the use of native RPS (RS type 2) is provided for reducing the circulating levels of 3-hydroxykynurenine.

[0093] In another aspect of the invention, the use of native RPS (RS type 2) is provided for treating Alzheimer's disease, Huntington's disease, Parkinson's disease, vitamin B6 deficiency, or for assisting individuals undergoing hydrocortisone treatment or pregnant individuals.

[0094] In another aspect of the invention, a method is provided for causing a reduction in the circulating level of amine histamine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of resistant potato starch based on a dosing regimen.

[0095] Thus, in this context, an "individual in need of such treatment" is an individual having increased histamine circulating levels compared to a control individual, for example, an individual with a baseline serum histamine level of more than 10 nmol / L, or an individual suffering from or prone to a heightened immune response, chronic urticaria, histamine intolerance, atopic eczema, food allergy, major depressive disorder, or idiopathic anaphylaxis.

[0096] In another aspect of the invention, the use of native RPS (RS type 2) is provided for reducing the circulating levels of histidine.

[0097] In another aspect of the invention, the use of native RPS (RS type 2) is provided for treating a heightened immune response, inflammation, itching, swelling, allergic reaction, chronic urticaria, histamine intolerance, mast cell activation syndrome, atopic eczema, allergy, food allergy, major depressive disorder, or idiopathic anaphylaxis.

[0098] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of the collagen degradation product 5-hydroxylysine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on a dosing regimen.

[0099] Thus, in this context, an "individual in need of such treatment" is an individual having increased 5-hydroxylysine circulating levels compared to a control individual, e.g., an individual having a baseline serum hydroxylysine level of greater than 0.24 μmol / L. Such individuals may suffer from diabetic nephropathy, viral hepatitis, progressive osseous heteroplasia, Paget's disease, chronic bronchitis, pneumonia, emphysema, compensated cirrhosis, mucopolysaccharidosis, irritable bowel syndrome, collagen metabolic disorders, have a genetic disease affecting collagen synthesis, be elderly, or otherwise be subjects exposed to environmental exposures that promote collagen degradation.

[0100] In another aspect of the invention, there is provided the use of native RPS (RS type 2) for reducing the circulating level of 5-hydroxylysine.

[0101] In another aspect of the invention, there is provided the use of native RPS (RS type 2) for treating diabetic nephropathy, viral hepatitis, progressive osseous heteroplasia, Paget's disease, chronic bronchitis, pneumonia, emphysema, compensated cirrhosis, mucopolysaccharidosis, irritable bowel syndrome, collagen metabolic disorders, or genetic diseases affecting collagen synthesis.

[0102] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of the collagen degradation product 4-hydroxyproline in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on a dosing regimen.

[0103] Thus, in this context, an "individual in need of such treatment" is an individual having increased 5-hydroxylysine or 4-hydroxyproline circulating levels as compared to a control individual, e.g., an individual having a baseline serum hydroxylysine level of greater than 13 μmol / L. Such individuals may suffer from McCune-Albright syndrome, Paget's disease, scleroderma, collagen metabolism disorders, have a genetic disease affecting collagen synthesis, be elderly, or otherwise be subjects whose skin is subjected to environmental exposures that promote collagen breakdown.

[0104] In another aspect of the invention, the use of native RPS (RS type 2) is provided for reducing the circulating level of 4-hydroxyproline.

[0105] In another aspect of the invention, the use of native RPS (RS type 2) is provided for treating McCune-Albright syndrome, Paget's disease, scleroderma, collagen metabolism disorders, or genetic diseases affecting collagen synthesis.

[0106] In another aspect of the invention, there is provided the use of native RPS (RS type 2) in an individual in need of such treatment for preventing collagen breakdown, comprising administering to the individual an effective amount of a resistant potato starch suitable based on a dosing regimen.

[0107] Thus, in this context, an "individual in need of such treatment" is an individual having increased 5-hydroxylysine or 4-hydroxyproline circulating levels as compared to a control individual, e.g., an individual having a baseline serum hydroxylysine level of greater than 13 μmol / L. Such individuals may suffer from McCune-Albright syndrome, Paget's disease, scleroderma, collagen metabolism disorders, have a genetic disease affecting collagen synthesis, be elderly, or otherwise be subjects whose skin is subjected to environmental exposures that promote collagen breakdown.

[0108] In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of polyamine N-acetylputrescine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen.

[0109] Thus, in this context, an "individual in need of such treatment" can be an individual having increased N-acetylputrescine levels compared to a control individual.

[0110] In another aspect of the invention, there is provided the use of native RPS (RS type 2) for reducing the level of N-acetylputrescine. In another aspect of the invention, there is provided a method of causing a decrease in the circulating level of polyamine N-acetylspermidine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on a dosing regimen.

[0111] Thus, in this context, an "individual in need of such treatment" can be an individual having increased N-acetylspermidine levels compared to a control individual, e.g., an individual having a baseline serum N-acetylspermidine level of more than 0.5 nmol / L, or an individual infected with or suspected of being infected with a coronavirus, or an individual having developed or at genetic risk of developing cancer, or an individual having developed or at genetic risk of developing a cardiovascular disease.

[0112] In another aspect of the invention, there is provided the use of native RPS (RS type 2) for reducing the level of N-acetylspermidine.

[0113] In another aspect of the invention, there is provided the use of native RPS (RS type 2) for reducing or decreasing the severity of, for example, one or more symptoms associated with coronavirus infection, such as dyspnea, coagulation, and symptoms requiring respiratory assistance, in the treatment of coronavirus infection.

[0114] In another aspect of the invention, there is provided a method of increasing the circulating levels of polyamines in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on an administration regimen.

[0115] In another aspect of the invention, there is provided a method of increasing the circulating levels of acylcarnitine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on an administration regimen.

[0116] Thus, in this context, an "individual in need of such treatment" is an individual having reduced circulating levels of acylcarnitine compared to a control individual.

[0117] According to another aspect of the invention, there is provided the use of native RPS (RS type 2) for increasing the circulating levels of acylcarnitine. In another aspect of the invention, there is provided a method of causing a decrease in the serum ratio of short-chain and medium-chain carnitine to free carnitine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a resistant potato starch suitable based on an administration regimen.

[0118] Thus, in this context, an "individual in need of such treatment" can be an individual having an increased ratio of short-chain and medium-chain carnitine to free carnitine compared to a control individual, an individual with impaired mitochondrial function, or an individual having intestinal permeability due to use of non-steroidal anti-inflammatory drugs (NSAIDs), chemotherapy, viral infections such as human immunodeficiency virus (HIV), as a complication of diabetes, or as a primary disease, or having a hypersensitivity intestinal disorder or an inflammatory bowel disease (e.g., Crohn's disease, or colitis).

[0119] In another aspect of the invention, the use of native RPS (RS type 2) is provided for reducing the ratio of short-chain and medium-chain carnitine to free carnitine.

[0120] In another aspect of the invention, the use of native RPS (RS type 2) is provided for treating mitochondrial dysfunction, for example, for reducing the production of reactive oxygen species (e.g., free radicals).

[0121] In another aspect of the invention, a method is provided for causing an increase in the circulating level of propionylcarnitine in an individual in need of such treatment, the method comprising administering to the individual an effective amount of resistant potato starch based on a dosing regimen.

[0122] Thus, in this context, an "individual in need of such treatment" is an individual having a decreased circulating level of propionylcarnitine compared to a control individual, for example, an individual having a baseline serum propionylcarnitine level of less than 0.39 μmol / L, or an athlete who is exercising or undergoing training to improve muscle strength and / or physical coordination, or a male in need of improvement in sexual ability, erectile function, or blood circulation.

[0123] According to another aspect of the invention, the use of native RPS (RS type 2) is provided for increasing the circulating level of acylcarnitine.

[0124] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for the improvement of sexual ability, improvement of erectile function, or blood circulation promotion.

[0125] In another aspect of the present invention, there is provided a method of increasing the circulating level of serotonin in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0126] Thus, in this context, an "individual in need of such treatment" is an individual having a reduced serotonin circulating level as compared to a control individual, for example, an individual having a baseline serum serotonin level of less than 50 ng / mL and experiencing a neurological condition such as anxiety or clinical depression.

[0127] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for increasing the circulating level of serotonin.

[0128] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for inhibiting monoamine oxidase (MAO) activity.

[0129] In another aspect of the present invention, there is provided a method of increasing the circulating level of coenzyme Q10 in an individual in need of such treatment, the method comprising administering to the individual an effective amount of a suitable resistant potato starch based on an administration regimen.

[0130] Thus, in this context, an "individual in need of such treatment" is an individual having reduced coenzyme Q10 circulating levels as compared to a control individual, for example, an individual having a baseline serum coenzyme Q10 level of less than 0.5 μmol / L, or an athlete, or an individual suffering from a heart disease such as migraine, congestive heart failure, hypertension, hypercholesterolemia, diabetes, or Parkinson's disease, or suspected of having the same, or an individual taking a statin agent and having statin-induced myopathy.

[0131] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for increasing the circulating levels of coenzyme Q10.

[0132] According to another aspect of the present invention, there is provided the use of native RPS (RS type 2) for improving mitochondrial function, reducing the effects of free radicals, and / or reducing the effects of oxidative stress.

[0133] According to another aspect of the present invention, there is provided a method for causing a reduction in the circulating levels of hydroxydodecanoic acid in an individual in need of such treatment, the method comprising administering to the individual an effective amount of resistant potato starch suitable based on an administration regimen.

[0134] Thus, in this context, an "individual in need of such treatment" is an individual having increased circulating levels of hydroxydodecanoic acid as compared to a control individual.

[0135] Therefore, in another aspect of the present invention, there is provided the use of native RPS (RS type 2) for decreasing the abundance of hydroxydodecanoic acid.

[0136] In some embodiments of the present invention, resistant potato starch is administered daily over a period of 1 to 12 weeks. In this context, "daily" does not necessarily mean "every day", for example, it means 19 days out of 20 days, 9 days out of 10 days, 17 days out of 20 days, 8 days out of 10 days.

[0137] As discussed herein, the effective amount can be, for example, 0.5 to 40 g, or 0.5 to 30 g, or 0.5 to 7 g, or 0.5 to 3.5 g of resistant starch.

[0138] Having described the preferred embodiments of the present invention above, it will be recognized and understood that various changes can be made therein, and the appended claims are intended to cover all such changes that can be included within the spirit and scope of the present invention.

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Claims

1. A suitable resistant potato starch for use in the treatment of an individual that requires the suppression of collagen degradation, or the reduction of 5-hydroxylysine levels, or the reduction of 4-hydroxyproline levels, wherein the suitable resistant potato starch is administered to the individual in an effective amount based on a dosage regimen.

2. The preferred resistant potato starch according to claim 1, wherein the individual requiring such treatment has a baseline serum hydroxylysine level greater than 0.24 μmol / L.

3. The preferred resistant potato starch according to claim 1, wherein the individual requiring such treatment has a baseline serum hydroxyproline level greater than 13 μmol / L.

4. The preferred resistant potato starch according to claim 1, wherein the individual requiring such treatment has a collagen metabolic disorder, a genetic condition affecting collagen synthesis, is elderly, or exposes its skin to environmental exposure that promotes collagen degradation, including ultraviolet radiation.

5. A suitable resistant potato starch for use in the treatment of an individual requiring a reduction in aminehistamine levels, wherein the suitable resistant potato starch is administered to the individual in an effective amount based on a dosage regimen.

6. The preferred resistant potato starch according to claim 5, wherein the individual requiring such treatment has a baseline serum histamine level greater than 10 nmol / L.

7. The preferred resistant potato starch according to claim 5, wherein the individual requiring such treatment has inflammation, itching, swelling, an allergic reaction, or is suffering from an allergy.

8. The preferred resistant potato starch according to claim 5, wherein the individual requiring such treatment has histamine intolerance and / or mast cell activation syndrome (MCAS).

9. The preferred resistant potato starch according to claim 5, wherein the individual requiring such treatment has excessive intestinal permeability and / or "leaky gut".

10. A suitable resistant potato starch for use in the treatment of an individual requiring an increase in the levels of the neurosteroid sulfate pregnenolone or 3-β-hydroxy-5-cholestic acid, wherein the suitable resistant potato starch is administered to the individual in an effective amount based on a dosage regimen.

11. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment has a baseline serum pregnenolone sulfate level of less than 40 ng / mL.

12. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment has menstrual-related migraines or headaches.

13. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment is a student, is studying, or requires enhancement of memory function.

14. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment has a baseline serum 3-β-hydroxy-5-cholestic acid level of less than 67 ng / mL.

15. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment has Alzheimer's disease or has a genetic risk of developing Alzheimer's disease.

16. The preferred resistant potato starch according to claim 10, wherein the individual requiring such treatment requires a modulator of gamma-secretase activity.

17. A suitable resistant potato starch for use in the treatment of an individual requiring a reduction in 3-hydroxykynurenine levels, comprising administering to the individual in an effective amount of the suitable resistant potato starch based on a dosage regime.

18. The preferred resistant potato starch according to claim 17, wherein the individual requiring such treatment has a baseline urinary 3-hydroxykynurenine level greater than 450 μg / g creatinine.

19. The preferred resistant potato starch according to claim 17, wherein the individual requiring such treatment has menstrual-related migraines or headaches.

20. The preferred resistant potato starch according to claim 17, wherein the individual requiring such treatment is receiving hydrocortisone treatment or is pregnant.

21. The preferred resistant potato starch according to claim 17, wherein the individual requiring such treatment is experiencing increased oxidative stress, has mitochondrial dysfunction, or has diabetes.

22. A suitable resistant potato starch for use in the treatment of an individual requiring an increase in serotonin levels in human serum, wherein the suitable resistant potato starch is administered to the individual requiring such treatment in an effective amount based on a dosage regimen.

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