Dietary composition for preventing and / or treating hypoolfaction and hypogustation

Abstract

A dietary composition for use in the prevention and / or treatment of hypoolfaction and hypogustation in a human subject, the dietary composition comprising: a) a simulated fasting dietary ingredient administered for a first period of time that provides less than 50% of calories of the subject's normal caloric intake while limiting proteins and sugars; and b) a reeating dietary ingredient administered over a second period of time, the reeating dietary ingredient providing 60-100% of calories of the subject's normal caloric intake, where the simulated fasting dietary ingredient and the reeating dietary ingredient are administered over a plurality of cycles.

Description

TECHNICAL FIELD

[0001] The present invention relates to the technical field of the pharmaceutical and dietetic industry.

[0002] In particular, the present invention relates to a dietetic composition for the prevention and / or treatment of hyposmia and hypogeusia. BACKGROUND

[0003] Obesity is one of the main risk factors for age-related diseases and has been rapidly growing in the United States, Europe and many countries. Attempts to reverse this epidemic have mostly failed, partly because lifestyle changes are not sustainable for most patients. 1 Chemoreception - i.e. taste and smell - is a key factor in the palatability of food for humans, which plays an important role in food selection and energy consumption 2 . Conversely, nutritional intake or eating habits affect taste and smell sensitivity 3 , as the tongue and olfactory bulb are organs associated with obesity and the function of the tongue and olfactory bulb is affected by biochemical mediators that promote obesity 4 . Thus, changes in taste perception are associated with an increase in body mass index (BMI) 3,5,6 , and olfactory impairment has been found in overweight (OW) and obese subjects. 7,8

[0004] In particular, hyposmia is one of the common diseases in obese subjects. Hyposmia or olfactory blunting indicates a decrease in the ability of the sense of smell to detect odors.

[0005] Due to the close link between taste and smell, many people with hyposmia also experience hypogeusia, i.e. a decrease in taste.

[0006] In fact, although hyposmic patients usually have a normal perception of salty, sweet, sour and bitter substances, hyposmic patients are unable to effectively distinguish these tastes, as this largely depends on normal olfaction.

[0007] Notably, many factors, such as high cholesterol, low insulin, low ghrelin and high leptin serum levels, are associated with the inhibitory effect of olfaction and taste performance in obese individuals. 4,5,7,8,14

[0008] Therefore, the technical problem addressed by the present invention is to provide a remedy that can treat and / or prevent hyposmia and hypogeusia to enhance or maintain the olfactory and gustatory performance of a subject, in particular an overweight subject. SUMMARY

[0009] The above problems are solved by providing a dietary composition for preventing and / or treating olfactory and gustatory hyporexia in a human subject. The dietary composition comprises:

[0010] a mimicked fasting dietary component, taken during a first time period, which provides less than 50% of the subject’s normal caloric intake, while limiting protein and sugar; and

[0011] a re-feeding dietary component, taken during a second time period, which provides 60-100% of the subject’s normal caloric intake;

[0012] wherein the mimicked fasting dietary component and the re-feeding dietary component are taken over a plurality of cycles.

[0013] Preferably, the dietary composition is taken by a human subject having a body mass index (BMI) > 25.

[0014] In particular, the dietary composition is taken by a human subject having a body mass index (BMI) equal to or greater than 25 and less than 40, preferably a BMI between 25 and 40, more preferably between 30 and 40.

[0015] In particular, the human subject is between 18 and 75 years old.

[0016] Preferably, the human subject has not or has not suffered from any kind of chemoperception disorder related to a previous COVID-19 infection.

[0017] Preferably, the first time period is between 2 and 10 days, preferably between 2 and 6 days, more preferably the first time period is 5 days, and / or the second time period is between 7 and 85 days, preferably between 25 and 26 days.

[0018] Within the meaning of the present invention, the term “normal caloric intake of the subject” refers to the amount of calories that the subject consumes to maintain its body weight.

[0019] The normal caloric intake of the subject can be estimated by interviewing the subject and / or taking into account the subject’s body weight.

[0020] As a rough guide, the normal caloric intake of the subject is 2600 kcal / day on average for men and 1850 kcal / day on average for women.

[0021] After taking the mimicked fasting dietary component, and optionally before taking the mimicked fasting dietary component, the human subject follows the re-feeding dietary component treatment, i.e. the patient follows its regular diet.

[0022] In the meaning of the present application, the term "regular diet" means that the human subject is not required to follow any specific predetermined diet regime, in particular during said second period of time.

[0023] For example, during said second period of time, the human subject can freely follow any balanced diet with caloric intake to maintain the body weight of these subjects, the caloric intake of the subjects being proportional to their gender, age, height and body activity habits.

[0024] Preferably, said re-feeding diet component provides 70-100% of the caloric intake of the subject, more preferably 90-100%.

[0025] Typically, in the FMD regimen, the daily diet of the subject is replaced every predetermined number of days (e.g. 5 days), once a month, during which the subject ingests the mimicked fasting diet component and is allowed to drink large amounts of water. For the following 25-26 days, these subjects receive the re-feeding diet component.

[0026] In one embodiment according to the present application, the mimicked fasting diet component is provided for 5 days and the re-feeding diet component is provided for 25-26 days every month for six consecutive cycles.

[0027] Preferably, the mimicked fasting diet component and the re-feeding diet component are administered for a plurality of cycles for a period of at least 6 months, preferably 6-12 months.

[0028] Preferably, the blood concentration of leptin is reduced by 5 to 18 ng / ml and / or the blood concentration of ghrelin is increased by 30 to 90 pg / ml when measured 6 months after the start of the administration of the diet composition compared to the blood concentration of leptin and / or ghrelin measured before the start of the administration of the diet composition, respectively.

[0029] Preferably, the blood concentration of leptin is reduced by 8 to 20 ng / ml and / or the blood concentration of ghrelin is increased by 220 to 290 pg / ml when measured 6 months after the start of the administration of the diet composition compared to the blood concentration of leptin and / or ghrelin measured before the start of the administration of the diet composition, respectively.

[0030] Preferably, the mimicked fasting diet component provides the subject with no more than 1200 kcal / day, more preferably the mimicked fasting diet component provides the subject with 600-1100 kcal / day.

[0031] Preferably, the first time period is 5 days and the fasting mimicking diet composition provides the subject with 800-1200 kcal / day of calories on the first day of the first time period and 600-800 kcal / day of calories from the second to the fifth day of the first time period.

[0032] Preferably, the fasting mimicking diet composition provides the subject with no more than 11 kcal / kg (body weight) / day of calories, more preferably 2-5 kcal / kg (body weight) / day.

[0033] In one embodiment, the fasting mimicking diet composition provides the subject with a protein content of less than or equal to 36 g / day, preferably 0-20 g / day.

[0034] In particular, the fasting mimicking diet composition provides the subject with a protein content of 36, 20, 10 or 5 or 0 g / day, in order of increasing preference.

[0035] According to a preferred embodiment, if carbohydrates are present in the fasting mimicking diet composition, these provide no more than half of the calories provided by the diet composition described above.

[0036] Preferably, the fasting mimicking diet composition comprises a protein content of less than 15% of the total calories provided by the fasting mimicking diet composition, more preferably less than 12%.

[0037] Preferably, the fasting mimicking diet composition comprises a sugar content of less than 50% of the total calories provided by the fasting mimicking diet composition, more preferably less than 48%.

[0038] Preferably, the fasting mimicking diet composition comprises a fat content of equal to or greater than 40% of the total calories provided by the fasting mimicking diet composition, more preferably less than 50%, even more preferably less than 48%.

[0039] Alternatively, the fasting mimicking diet composition comprises a fat content of between 40% and 80% of the total calories provided by the fasting mimicking diet composition.

[0040] Preferably, the fasting mimicking diet composition comprises at least 45% of the calories from fatty acids and up to 5% of the calories from plant-based proteins and up to 50% of the calories from carbohydrates.

[0041] In one embodiment, the fasting mimicking diet composition provides the human subject with the following energy intake as shown in Table 1 below:

[0042] Day 1 Days 2, 3, 4, 5 Total calories (kcal) 800-1200 600-800 Fat 40-48％ 40-47％ Carbohydrate 40-45％ 45-50％ Protein 9-13％ 7-11％

[0043] Table 1

[0044] Preferably, the fasting mimicking diet ingredients comprise complex carbohydrates from plant sources, which more preferably comprise soy, rice or other grains.

[0045] Preferably, at least 50% of the calories in the fasting mimicking diet ingredients come from fatty acids, which come from coconut oil and tree nuts. Tree nuts more preferably comprise walnuts, macadamia nuts and / or almonds.

[0046] Preferably, the fasting mimicking diet ingredients comprise high amounts of monounsaturated and polyunsaturated fats, and, as mentioned before, reduced amounts of proteins and sugars.

[0047] Examples of FMDs can be found in the publications WO 2014 / 066426 and WO 2014 / 12700.

[0048] Advantageously, the FMD cycles show reduced plasma levels of glucose, insulin-like growth factor 1 (IGF-1) and insulin, improved blood lipids, reduced visceral fat and modulated pro-inflammatory cytokines, particularly in subjects with high baseline levels of these markers.

[0049] In particular, with the fasting mimicking diet ingredients, the human subject eats food with high amounts of monounsaturated and polyunsaturated fats and lower amounts of proteins and sugars (as mentioned before, > 40% of the calories come from fat). Diets based on these specific nutrients and caloric intakes have similar beneficial effects to those of fasting.

[0050] Advantageously, as detailed in the experimental part of the present disclosure, by taking the diet composition according to the present application, the sensitivity of taste and smell is improved and this improvement is detectable even several months after the end of the cycles mentioned above.

[0051] Moreover, the fasting mimicking diet ingredients enable the reduction of leptin and the increase of ghrelin.

[0052] Interestingly, unlike the baseline in FMD, ghrelin, leptin and insulin were still significantly different after 6 months of follow-up, leading to the hypothesis that patients changed their nutritional habits after the FMD intervention and / or that many of the effects of FMD are long-lasting.

[0053] It is known that the levels of leptin and ghrelin have an impact on the regulation of obesity and, therefore, on the chemoperception regulation, in particular the olfactory and gustatory regulation. In fact, the reduction of leptin and the increase of ghrelin enable the reduction of appetite and the increase of satiety, thus contributing to weight loss.

[0054] It is known that an imbalance of leptin and ghrelin affects obesity. 9Due to the higher body fat percentage of obese individuals, obese individuals typically exhibit higher circulating concentrations of leptin than normal weight individuals.

[0055] Therefore, also disclosed is a dietary composition for preventing and / or treating olfactory and / or gustative hyporexia in a human subject, the dietary composition comprising a fasting mimicking diet component, which is to be taken over a predetermined period of time.

[0056] Preferably, the dietary composition is taken by a human subject having a body mass index (BMI) > 25.

[0057] In particular, the dietary composition is taken by a human subject having a body mass index (BMI) equal to or greater than 25 and less than 40, preferably a BMI between 25 and 40, more preferably between 30 and 40.

[0058] In particular, the fasting mimicking diet component provides less than 50% of the normal caloric intake of the subject, while limiting proteins and sugars, wherein the fasting mimicking diet component is taken over a plurality of cycles.

[0059] Preferably, the predetermined period of time is between 2 and 10 days, preferably between 2 and 6 days, more preferably the predetermined period of time is 5 days, and the plurality of cycles comprises taking once a month for at least 6 months, preferably 6-12 months.

[0060] In one embodiment according to the present application, the fasting mimicking diet component is taken over a predetermined number of days (e.g. 5 days), once a month. The fasting mimicking diet component is not provided for the following 25-26 days.

[0061] Preferably, the fasting mimicking diet component is taken over a plurality of cycles for at least 6 months, more preferably 6-12 months.

[0062] Preferably, the fasting mimicking diet component provides the subject with no more than 1200 kcal / day, more preferably the fasting mimicking diet component provides the subject with 600-1100 kcal / day.

[0063] Preferably, the predetermined period of time is 5 days, and said fasting mimicking diet component provides the subject with 800-1200 kcal / day on the first day of said predetermined period of time, and 600-800 kcal / day on the second to fifth day of said predetermined period of time.

[0064] Preferably, the fasting mimicking diet component comprises at least 45% of the calories from fatty acids and up to 5% of the calories from proteins, in particular plant-based proteins, and up to 50% of the calories from carbohydrates.

[0065] Preferably, the mimicking-fasting dietary component provides the human subject with the following energy intake as shown in Table 1 above.

[0066] According to the present application, the above-mentioned problems are also solved by providing a dietary composition for preventing and / or treating a disease or disorder or condition involving leptin and / or ghrelin imbalance in a human subject, the dietary composition comprising:

[0067] a mimicking-fasting dietary component to be taken during a first period of time, the mimicking-fasting dietary component providing less than 50% of the subject's normal caloric intake, while limiting protein and sugar; and

[0068] a re-feeding dietary component to be taken during a second period of time, the re-feeding dietary component providing 60-100% of the subject's normal caloric intake,

[0069] wherein the mimicking-fasting dietary component and the re-feeding dietary component are taken over a plurality of cycles.

[0070] Preferably, the disease or disorder or condition involving leptin and / or ghrelin imbalance in a human subject is selected from the group consisting of overweight or obesity.

[0071] Preferably, the first period of time is from 2 to 10 days, preferably from 2 to 6 days, more preferably the first period of time is 5 days, and / or the second period of time is from 7 to 85 days, more preferably from 25 to 26 days.

[0072] In one embodiment according to the present application, 5 days per month provide the mimicking-fasting dietary component and 25-26 days per month provide the re-feeding dietary component, for six consecutive cycles.

[0073] Preferably, the mimicking-fasting dietary component and the re-feeding dietary component are taken over a plurality of cycles for a period of at least 6 months, preferably from 6 to 12 months.

[0074] Preferably, the blood concentration of leptin is reduced by 5 to 18 ng / ml and / or the blood concentration of ghrelin is increased by 30 to 90 pg / ml 6 months after the start of taking the dietary composition according to the present application over a plurality of cycles, when compared to the blood concentration of leptin and / or ghrelin measured before the start of taking the dietary composition.

[0075] Preferably, the blood concentration of leptin is reduced by 8 to 20 ng / ml and / or the blood concentration of ghrelin is increased by 220 to 290 pg / ml 6 months after the start of taking the dietary composition according to the present application over a plurality of cycles, when compared to the blood concentration of leptin and / or ghrelin measured before the start of taking the dietary composition.

[0076] Preferably, the simulated fasting diet provides the subject with no more than 1200 kcal / day of energy; more preferably, the simulated fasting diet provides the subject with 600-1100 kcal / day of energy.

[0077] Preferably, the first time period is 5 days, and the simulated fasting diet provides the subject with 800-1200 kcal / day of energy on the first day of the first time period, and 600-800 kcal / day of energy on the second to fifth days of the first time period.

[0078] Preferably, the components of the simulated fasting diet include at least 45% of the calories from fatty acids, up to 5% of the calories from protein, especially plant-based protein, and up to 50% of the calories from carbohydrates.

[0079] Preferably, the simulated fasting diet components provide the following energy intake to human subjects, as shown in Table 1 above.

[0080] The present invention will be further described in conjunction with the accompanying drawings and some embodiments, which are provided below for illustrative and non-limiting purposes. Attached Figure Description

[0081] Figure 1 The diagram shows the CONSORT report for 113 participants. Of these, 102 were enrolled in the clinical study and randomly assigned to two groups. Group 1 (FMD→Control, n=50) participants began a simulated fasting diet (FMD) after randomization. FMD components were provided for 5 days each month for six consecutive cycles. Group 2 (Control→FMD, n=52) participants maintained a normal diet for a 6-month monitoring period. After the first 6-month period, these participants transitioned to FMD cycle therapy. Data were collected at enrollment (T0), at the first 6-month period (T1), and at the second 6-month period (T2). At the end of each 6-month FMD phase, data were collected 5 days after the participants resumed a normal diet following the sixth FMD cycle.

[0082] Figure 2 shows the chemical perception tests for the two groups. Figure 2A The study reported differences (Δ) in chemosensory and biochemical tests in participants before and after taking FMD (n=78, FMD 1=FMD→40 participants in the control group, therefore at T1, FMD 2=Control→38 participants in the FMD group, therefore at T2) and in participants before and after the 6-month observation period (in the control group, n=47 participants in the FMD group, at T1) while on a regular diet (control). Figure 2BThis study reports the percentage of participants whose antidiabetic and antihypertensive medications changed after a 6-month period of simulated fasting diet (FMD) or a regular diet (control). All data are presented as mean ± SD. TDI, total olfactory score; TTS, total taste score; ng, nanograms; ml, milliliters; %, percentage; FMD, simulated fasting diet; T0, baseline; T1, after 6 months of FMD.

[0083] Figure 3 The scatter plot (median line) depicts changes in major chemosensory tests and biochemical regulators in participants from FMD → Control (FMD 1, n = 40) and Control → FMD (FMD 2, n = 38) at baseline and after 6 months of fasting-mimicking diet (FMD) versus control diet (n = 47). An asterisk indicates a significant difference within the study group (the exact p-value is given in the text). ng, nanogram; pg, picogram; ml, milliliter; μU, micro international unit; TTS, total taste score; TDI, comprehensive olfactory score. The exact p-value is given in the specific implementation details.

[0084] Figure 4 This represents the major inter-group changes in chemosensory perception at baseline (T0) after the first 6 months (T1) of FMD→Control participants following a fasting-simulated diet and Control→FMD participants maintaining a normal diet, and the second 6 months (T2) of the FMD→Control and Control→FMD crossover. Dashed boxes indicate significant inter-group differences (exact p-values ​​are given in the specific implementation). Values ​​are given as the mean of the 95% CI. OT, Odor Threshold; TTS, Total Taste Score; TDI, Comprehensive Olfactory Score. Detailed Implementation

[0085] This invention relates to a dietary composition for the prevention and / or treatment of decreased sense of smell, as described above. As described above, the dietary composition is administered to subjects with a BMI ≥ 25 and an age between 18 and 75 years.

[0086] For the purposes of this invention, the following acronyms have the following meanings:

[0087] abbreviation

[0088] Fasting-simulated diet (FMD)

[0089] Clinical Trial Reporting Guidelines CONSORT

[0090] Time 0, begin researching T0

[0091] Time 1, T1 six months later

[0092] Time 2, Research ends T2

[0093] Body Mass Index (BMI)

[0094] Ear-nose-throatENT

[0095] TDI Composite Score TDI TTS Overall Score TTS

[0096] Insulin-like growth factor IGF-1

[0097] Insulin-like growth factor binding protein IGFBP-1

[0098] Odor threshold OT

[0099] Odor identification OD

[0100] Odor recognition OI

[0101] Alanine aminotransferase (ALT)

[0102] Aspartate aminotransferase (AST)

[0103] Waist WC

[0104] Fat content FM

[0105] Skeletal muscle mass (MM)

[0106] Visceral fat VF

[0107] Steady-state model evaluation HOMA

[0108] Erythrocyte sedimentation rate (ESR)

[0109] As previously reported, after treatment with components of a simulated fasting diet, subjects were given a refeeding diet, meaning patients followed their regular diet. Specifically, during the second time period, patients were not required to adhere to any specific pre-defined dietary regimen.

[0110] Materials and methods

[0111] Eligible patients

[0112] 113 white adults with a BMI of 25 or higher were recruited.

[0113] Inclusion criteria were BMI ≥ 25 and age between 18 and 75 years. All participants underwent general clinical and ear, nose, and throat (ENT) examinations. Chemosensory disturbances associated with a previous COVID-19 infection were considered exclusion criteria prior to enrollment. Current or recent smokers (who quit less than 3 years ago), those with allergies, and those with a history of ENT surgery were excluded. Individuals with major systemic or organ failure diseases (including neurodegenerative, psychiatric, and cardiovascular diseases, non-diabetic liver disease, type 1 diabetes, pancreatic diabetes, or steroid-induced diabetes) were also excluded based on medical history, physical and neuropsychological examination, and complete blood count.

[0114] Other exclusion criteria include:

[0115] - Acute infection / fever, history of cancer within 5 years prior to the study.

[0116] - Infectious hepatitis B, C, or E, HIV infection,

[0117] - Autoimmune diseases or immunosuppressive therapy

[0118] - Participate in other interventional studies

[0119] - Anemia or blood disorders

[0120] - Polyneuropathy (autoimmune diseases, alcohol-related diseases, vitamin B12 deficiency, connective tissue diseases),

[0121] - Pacemaker and food allergies (nuts, tomatoes, soy, or other ingredients in the diet plan),

[0122] - Gastrointestinal / eating disorders and surgery (excluding Helicobacter pylori by C13 urea breath test, and also excluding history of appendectomy) and

[0123] - History of taste and / or olfactory disorders,

[0124] -Pregnant and breastfeeding women, 4,7

[0125] - Participants with anosmia (i.e., TDI ≤ 16.5), 17

[0126] - Participants with geriatric aphasia.

[0127] In addition, vegetarianism / veganism, continued use of drugs that affect chemical perception, and drug / alcohol abuse were considered exclusion criteria.

[0128] Randomization and masking

[0129] Eligible participants were randomly assigned to two different experimental groups. Specifically, one group started with a fasting-mimicking diet (FMD) component, followed by a refeeding component, and after 6 months (thus, according to the invention, 6 cycles of dietary component administration), these subjects were observed on a regular diet for an additional 6 consecutive months (FMD-control). The other group started with a regular diet, followed by treatment with the FMD component, then the refeeding component, and continued taking the dietary component according to the invention for 6 cycles (control-FMD).

[0130] One cycle of the treatment consists of administering the FMD ingredient to the patient for five consecutive days, followed by a refeeding component for the next 25 days.

[0131] Dietary therapy

[0132] FMD is a plant-based diet designed to reduce serum glucose and insulin-like growth factor-1 (IGF-1) to fasting-like levels and increase insulin-like growth factor binding protein-1 (IGFBP-1) and ketone bodies, while providing macronutrients and micronutrients to minimize the burden and adverse effects of fasting. 12

[0133] As mentioned earlier, take FMD ingredient (L-Nutra) for 5 consecutive days. www.prolonfmd.com), and FMD ingredients include vegetable-based food formulations, namely soups, energy bars, energy drinks, potato chips, teas, and supplements that provide high levels of minerals, vitamins, and essential fatty acids.

[0134] The simulated fasting diet provided subjects with approximately 4600 kJ of energy, or 1099 kcal (11% protein, 46% fat, and 43% carbohydrates) on day 1, and approximately 3000 kJ of energy, or 717 kcal (9% protein, 44% fat, and 47% carbohydrates) per day from day 2 to day 5.

[0135] All food consumed each day was individually packaged to allow participants to choose when to eat, while avoiding accidental ingestion of food components from the following day and reducing the risk of consuming food from other sources besides the packaged food. FMD components were started on the first possible day after the baseline visit ended.

[0136] Discontinue oral antidiabetic treatment while taking FMD ingredients. 13 If low blood pressure occurs (systolic blood pressure below 100 mmHg and diastolic blood pressure below 60 mmHg), the antihypertensive medication should be reduced. All participants were instructed to avoid excessive physical activity while taking the FMD ingredients and to resume normal exercise after taking the medication.13

[0137] Participants must record any other food or beverage they consume over a five-day period, excluding the provided meal pack. 13,16

[0138] Main results

[0139] Chemical perception test

[0140] Olfactory function is assessed through an olfactory function test, specifically using commercially available Sniffins. Test kits (Sniffin' Sticks; Burghart Instruments, Wedel, Germany) were used to evaluate olfactory performance in clinical and research settings. 18 Olfactory function tests include subtests for odor threshold (OT), odor discrimination (OD), and odor identification (OI), which relate to different aspects of olfactory processing in the neural flow from the olfactory bulb to the olfactory cortex. 19 The interval between consecutive subtests is 3 to 5 minutes. 20 The score ranges from 0 to 16. The average of the three subtests is the TDI composite score, which reflects general olfactory ability. Therefore, the score ranges from 0 to 48, with higher scores indicating stronger function. 17 Furthermore, according to normative data, olfactory performance is classified as abnormal when the TDI value is less than the 25th percentile. This value is based on age and sex (grouped for 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, and 71-80 years old, with cutoff values ​​of 32.35, 33.5, 33.5, 32.5, 30.75, 29.13, and 25.5 for women and 30.75, 32.75, 32.76, 30.44, 29.25, 28.5, and 22.75 for men). 21,22

[0141] In addition, each group participated in a taste test, namely a taste test strip. The taste test is a semi-quantitative, accurate, rapid, and simple tool used to study the threshold of the sides of the tongue for each of four basic taste enhancers. These taste enhancers were administered to patients at increasing concentrations (sweet: 0.05, 0.1, 0.2, and 0.4 g / ml sucrose; sour: 0.05, 0.09, 0.165, and 0.3 g / ml citric acid; salty: 0.016, 0.04, 0.1, and 0.25 g / ml sodium chloride; bitter: 0.0004, 0.0009, 0.0024, and 0.006 g / ml quinine hydrochloride). The taste test involved impregnating filter paper strips (“taste test strips”, Burghart Instruments, Wedel, Germany) with specific amounts of the four basic taste enhancers: sweet, sour, salty, and bitter. 23 The patient extends their tongue and places the test strip on the left or right side of the front third of the tongue (32 tests). Rinse mouth with water before each test. Participants must identify flavors from a list of four flavor enhancers using a multiple forced selection method (i.e., participants can only indicate one of the flavor enhancers mentioned in the list, assigning a score of 1 or 0 depending on whether the response is correct or incorrect). The sum of the number of correctly identified flavor enhancers on each side (ranging from 0 to 16 per side) is used to obtain the total number of flavor enhancers identified (TTS composite score), ranging from 0 to 32. 23 Based on normative data, taste performance was classified as abnormal when the TTS value was less than the 10th percentile. This value was based on age and sex (the cutoff values ​​for women were 19, 15, and 10.2 for the 18-40, 41-60, and over 60 age groups, and for men were 17, 9, and 9).

[0142] Secondary results

[0143] Biochemical testing

[0144] Baseline laboratory parameters, including serum glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), conjugated and unconjugated bilirubin, urea, and serum creatinine, measured under standardized conditions. Specifically, 5 mL of blood was drawn from the antecubital vein using a heparinized vacuum tube. The collected samples were centrifuged at 3000 x g for 5 minutes to separate the plasma, and all plasma samples were stored in multiple fractions and immediately frozen at -80°C until testing within one month of collection. 7

[0145] pass Insulin was analyzed using the e801 (Roche Diagnostics Italia Spa, Monza (MB), Italy) analytical unit, a high-throughput immunochemistry module. Leptin levels were measured using an enzyme immunoassay (ELISA) kit (catalog number: EH0216; FineTest, Wuhan, China), ghrelin and IGF-1 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (catalog number: EH0355; FineTest, Wuhan, China), and human IGF-1 (insulin-like growth factor 1) was measured using an ELISA kit (catalog number: EH0165; FineTest, Wuhan, China).

[0146] All samples and standards were analyzed using an Infinite M200 microplate reader and spectrophotometer (Tecan Group Ltd.). (Switzerland) to take readings. 7 Homeostasis model assessment of insulin resistance (HOMA-IR), homeostatic β-cell function (%B), and insulin sensitivity (%S) was performed using the HOMA2 calculator based on fasting insulin and glucose. 24,25

[0147] Anthropometry

[0148] During the clinical study, the same examiner used a scale (Seca model 700; Seca GmbH, Hamburg, Germany) and a rangefinder (Holtain Ltd, UK) to measure height and weight. 26,27 During the measurement, subjects wore only underwear. BMI was calculated by dividing weight (kg) by height (m), and BMI was expressed as kg / m². 2 The waist circumference (WC) was measured twice in a standing position using a non-elastic measuring tape, while the participant was instructed to exhale gently at the midpoint between the top of the iliac crest and the lower edge of the ribs. 28 Estimates of fat mass (FM, in % and kg), skeletal muscle mass (MM, in % and kg), and visceral fat level (VF level) were calculated based on a bioelectrical impedance analysis (BIA) device (Omron HBF-500BIA, Omron Medizintechnik, Mannheim, Germany). 54,55

[0149] result

[0150] 102 eligible patients were selected from 113 patients. Specifically, 50 and 52 participants were randomly assigned to the FMD→control group and the control→FMD group, respectively. Figure 1(Table 2). In the FMD→Control and Control→FMD groups, 16% (n=8) and 14.8% (n=7) of participants, respectively, reported not adhering to 6 cycles of FMD treatment. Figure 1 Following the 6-month FMD period, comparing the combined scores of smell (TDI) and taste (TTS) between participants with improved and deteriorating health status, as well as the TTS scores after the control period, revealed no differences in baseline primary parameters. Conversely, after the control period, participants with deteriorating TDI had significantly lower baseline BMI, weight, and WC compared to those with improved TDI (more information below). No participants experienced taste impairment at T0, T1, and T2, while 36% (18 / 50), 10% (4 / 40), and 13.5% (5 / 37) of participants in the FMD → control group, and 32% (17 / 52), 40% (19 / 47), and 2.6% (1 / 38) of participants in the control → FMD group, respectively, experienced olfactory impairment. Therefore, at the end of the 6 FMD cycles, the total number of subjects with hyposmia in Group 1 and Group 2 decreased from 37 out of 97 or 38.1% to 5 out of 78 or 6.4%, a reduction of 5.9 times (Figure 2).

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] Table 2. Aspects and characteristics of the sociodemographic population of all participants at baseline.

[0157] Values ​​of normally distributed variables are expressed as mean ± standard deviation (SD) and ± 95% confidence interval (CI), or values ​​of log-normally distributed variables are expressed as mean ± standard deviation (SD) and ± median (interquartile range; IQR), and values ​​of categorical variables are expressed as mean ± standard deviation (SD) and ± frequency n (%). BMI (Body Mass Index); OSAS (Obstructive Sleep Apnea Syndrome); ACEIs (Angiotensin-Converting Enzyme Inhibitors); ARBs (Angiotensin II Receptor Blockers); NSAIDs (Nonsteroidal Anti-inflammatory Drugs); PPIs (Proton Pump Inhibitors). OT, Odor Threshold; OD, Odor Discrimination; OI, Odor Identification; and the sum of OT, OD, and OI (TDI); TTS, Taste Score; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; TGs, Triglycerides; HDL, High-Density Lipoprotein Cholesterol; LDL, Low-Density Lipoprotein Cholesterol; ESR, Erythrocyte Sedimentation Rate; CRP, C-Reactive Protein; HOMA%B, Homeostatic Beta-Cell Function; HOMA%S, Insulin Sensitivity; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; WC, Waist Circumference; BMI, Body Mass Index; ng, Nanogram; pg, Pictogram; ml, Milliliter; mg, Milligram; dl, Deciliter; U, International Unit; μU, Micro International Unit; mm, Millimeter; L, Liter; h, Hour; cm, Centimeter; m, Meter; kg, Kilogram; %, Percentage; FM, Fat Mass; MM, Skeletal Muscle Mass; X 2 Chi-square. A p-value < 0.01 is considered significant. * Estimated by bioelectrical impedance analysis.

[0158] Changes in chemical perception testing:

[0159] Changes from baseline

[0160] After 6 FMD cycles, significant increases were observed in subject-specific analyses of surface odor threshold (OT), odor discrimination (OD), TDI, TTS, and sweetness in the FMD→control participants (n=40) (Table 3). Figure 3 As expected, no significant differences were found between the control → FMD participants (n=47) when comparing the results at T0 and T1 (during the normal eating period). Conversely, when comparing the results at T2 with those at T1 (patients = 38), the effects of 6 FMD cycles resulted in a significant increase in OT, OD, TDI, TTS, and sourness in the control → FMD group (Table 4). Figure 3Similar to the FMD→control group at T1 and T0. During the first 6 months (normal diet), compared with the control→FMD participants, all participants showed significant increases in ΔOT, ΔOD, ΔOdor Identification (OI), ΔTDI, ΔSweetness, ΔSourness, ΔBitterness, ΔSaltness, and ΔTTS after taking the FMD component 6 times (FMD→control + control→FMD) (Table 3, Figure 2).

[0161] Many markers between groups showed no difference at T2. When comparing the FMD→control group values ​​at T2 with the FMD→control group values ​​at T0 (n=37), significant differences were found in some chemical perception test variables: TDI (p=0.001), TTS (p=0.004), and sweetness (p<0.001), while no significant differences were found in OT (p=0.017), OD (p=0.015), OI (p=0.19), sourness (p=0.019), saltiness (p=0.34), and bitterness (p=0.1). At T2, after 6 months of resuming a regular diet, no significant differences were found in OT (p=0.66), OD (p=0.86), OI (p=0.94), TDI (p=0.69), sweet (p=0.79), sour (p=0.92), bitter (p=0.23), salty (p=0.54), and TTS (p=0.73) among the participants in the FMD→control group, especially when compared with the results at T1.

[0162] When patients with T2-level control → FMD were compared with those with T0-level control → FMD, similar behavior was observed, showing significant increases in OT (p<0.001), OD (p=0.002), TDI (p<0.001), TTS (p<0.001), sweetness (p<0.001), and sourness (p<0.001).

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Table 3. Baseline changes in chemosensory tests, biochemical assays, and anthropometry in participants who completed the trial.

[0176] FMD 1, FMD → control; FMD 2, control → FMD. Odor threshold (OT); Odor discrimination (OD); Odor identification (OI); and the sum of OT, OD, and OI (TDI); Taste score (TTS); Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Triglycerides (TGs); High-density lipoprotein cholesterol (HDL); Low-density lipoprotein cholesterol (LDL); Erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); Homeostatic β-cell function (HOMA%B); Insulin sensitivity (HOMA%S); Homeostatic model assessment of insulin resistance (HOMA-IR); Waist circumference (WC); Body mass index (BMI); ng (nanogram); pg (picogram); ml (milliliters); mg (milligrams); dl (deciliters); U (International units); μ (microinternational units); mm (millimeters); L (liters); h (hours); cm (centimeter); m (meter); kg (kilograms); % (percentage); Fat mass (FM); Skeletal muscle mass (MM); Visceral fat (VF). * Estimated by bioelectrical impedance analysis. Values ​​of normally distributed variables are expressed as mean ± standard deviation (SD) and ± 95% confidence interval (CI), while values ​​of log-normally distributed variables are expressed as mean ± standard deviation (SD) and ± median (interquartile range; IQR). Paired two-tailed t-tests were used to calculate p-values ​​for comparing changes within groups (p-value < 0.01 was considered significant). Two-tailed two-sample t-tests were used to compare the combined difference (Δ) in FMD 1 and FMD2 (n = 78) between participants and the control → FMD T0 - T1 (control diet) Δ value (n = 47) (p-value < 0.01 was considered significant).

[0177] Between-group analysis

[0178] Intergroup analysis showed that after 6 FMD cycles, compared with participants transitioning from control to FMD, participants in the control group showed significant increases in OT (p<0.001), OI (p=0.015), TDI (p<0.001), and sweetness (p<0.001) and TTS (p=0.007). Although increased perception of sourness (p=0.018) and bitterness (p=0.02) was observed, there were no significant intergroup changes in OD (p=0.28) and saltiness (p=0.1) (Table 4). Figure 4 After the second 6-month period, participants in the control → FMD group underwent 6 FMD cycles, while participants in the FMD → control group followed a regular diet but stopped the FMD cycles. Only the control → FMD group had a significantly higher OD (12.86 ± 1.39) than the FMD → control group (11.87 ± 1.83) (p = 0.01). These results indicate that the effects of the FMD cycle in the FMD → control group are durable.

[0179]

[0180]

[0181] Table 4. Intergroup comparisons of chemosensory tests, biochemical assays, and anthropometry at T0, T1, and T2 for all participants.

[0182] Odor threshold (OT); Odor discrimination (OD); Odor identification (OI); and the sum of OT, OD, and OI (TDI); Taste score (TTS); Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Triglycerides (TGs); High-density lipoprotein cholesterol (HDL); Low-density lipoprotein cholesterol (LDL); Erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); Homeostatic β-cell function (HOMA%B); Insulin sensitivity (HOMA%S); Homeostatic model assessment of insulin resistance (HOMA-IR); Waist circumference (WC); Body mass index (BMI); ng (nanogram); pg (picogram); ml (milliliters); mg (milligrams); dl (deciliters); U (International Units); μU (microinternational units); mm (millimeters); L (liters); h (hours); cm (centimeter); m (meter); kg (kilograms); % (percentage); Fat mass (FM); Skeletal muscle mass (MM); Visceral fat (VF). * Estimated by bioelectrical impedance analysis. The values ​​of normally distributed variables are expressed as mean ± standard deviation (SD) and ± 95% confidence interval (CI), or the values ​​of log-normally distributed variables are expressed as median (interquartile range; IQR).

[0183] Changes in cardiac metabolism and anthropometric variables

[0184] Changes from baseline

[0185] At the end of the 6-month FMD period, compared with baseline values ​​at T0, participants in the FMD→control group (n=40) showed significant decreases in leptin, IGF-1, total cholesterol, low-density lipoprotein (LDL), serum glucose, insulin, insulin sensitivity (HOMA%S), homeostasis model assessment of insulin resistance (HOMA IR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), waist circumference (WC), estimated fat mass (FM), and visceral fat (VF), while hunger hormone and estimated muscle mass (MM) (Omron HBF-500BIA, Omron Medizintechnik, Mannheim, Germany) significantly increased (Table 3). Figure 3 Similar changes were observed when comparing the participants in the control → FMD group (n=38) at T2 with those at T1, thus, as expected, no significant differences were found in the control → FMD group (n=47) when comparing the participants at T1 and T0 (control periods) (Table 3). Figure 3 A comparison of changes during the first 6 months (with normal food intake) between all participants receiving FMD treatment (FMD→Control + Control→FMD) and those receiving Control→FMD showed that patients experienced significant decreases in leptin, IGF-1, total cholesterol, LDL cholesterol, triglycerides (TGs), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum glucose, insulin, HOMAIR, AST, ALT, urea, and serum creatinine after the 6-month FMD cycle, while ghrelin and HOMA%S were found to be significantly increased (Table 3, Figure 2). Finally, in the same comparison, WC, body weight, BMI, FM (% and KG), and VF levels were significantly decreased, while MM was significantly increased (Table 3).

[0186] When the values ​​at T2 and T0 were also compared between the FMD→control participants (n=37), significant differences were found in the following variables: leptin (p=0.006), ghrelin (p=0.003), total cholesterol (p<0.001), insulin (p=0.002), ALT (p=0.005), HOMA%S (p=0.008), HOMA IR (p=0.002), estimated FM (% and Kg, p=0.006 and p=0.001, respectively), and estimated MM% (p<0.001).

[0187] In the same comparison, no significant differences were found in the following variables: IGF-1 (p=0.24), high-density lipoprotein (HDL) (p=0.65), LDL (p=0.012), TGs (p=0.06), AST (p=0.015), ESR (p=0.3), CRP (p=0.19), serum glucose (p=0.13), conjugated bilirubin (p=0.49) and unconjugated bilirubin (p=0.86), urea (p=0.21), serum creatinine (p=0.23), homeostatic β-cell function (HOMA%B) (p=0.14), body weight (p=0.12), WC (p=0.013), BMI (p=0.1), estimated MM Kg (p=0.05), and VF level (p=0.02). At the end of the second 6-month (T2) period after the FMD→control participants resumed their dietary habits, no significant differences were found in the following variables compared to the T1 values: leptin (p=0.23), IGF-1 (p=0.16), ghrelin (p=0.13), serum glucose (p=0.19), insulin (p=0.27), total cholesterol (p=0.98), LDL (p=0.52), HDL (p=0.63), TGs (p=0.75), ESR (p=0.3), CRP (p=0.42), conjugated bilirubin (p=0.83) and unconjugated bilirubin (p=0.47), AST (p=0.93), ALT (p=0.83), urea (p=0.85), serum creatinine (p=0.92), HOMA%B (p=0.74), HOMA%S (p=0.39), and HOMA IR (p = 0.23), WC (p = 0.54), body weight (p = 0.51), BMI (p = 0.49), and VF level (p = 0.59) were compared. Significant increases and decreases were found in estimated FM (% and Kg, p < 0.001 and p < 0.001, respectively) and MM (% and Kg, p < 0.001 and p = 0.013, respectively).

[0188] As shown in the FMD→control group, in the control→FMD group (n=38), when comparing the values ​​at T2 with those at T1, leptin (p<0.001), IGF-1 (p=0.004), serum glucose (p<0.001), insulin (p=0.002), total cholesterol (p<0.001), low-density lipoprotein (p<0.001), AST (p=0.002), ALT (p=0.009), urea (p<0.001), HOMA IR (p=0.002), WC (p<0.001), BMI (p=0.006), and estimated FM (% and Kg, both p<0.001) and VF levels (p=0.002) were all significantly reduced. Furthermore, significantly increased levels of hunger hormone (p<0.001), HDL (p=0.002), HOMA%S (p=0.005), and estimated MM (% and Kg, p=0.001 and p=0.002, respectively). No significant differences were found in TG (p=0.03), ESR (p=0.018), CRP (p=0.3), conjugated bilirubin (p=0.09) and unconjugated bilirubin (p=0.36), serum creatinine (p=0.16), HOMA%B (p=0.79), and body weight (p=0.06) (Table 3). Figure 3 When the values ​​at T2 were compared with those at T0, many parameters were found to be significantly decreased: leptin (p<0.001), serum glucose (p=0.001), insulin (p=0.002), total cholesterol (p<0.001), low-density lipoprotein (p<0.001), AST (p=0.002), ALT (p=0.011), urea (p<0.001), HOMA IR (p=0.003), WC (p=0.002), BMI (p=0.006), and estimated FM (% and Kg, both p<0.001) and VF levels (p=0.001); conversely, ghrelin (p<0.001), HOMA %S (p=0.008), and estimated MM (% and Kg, both p<0.001) were found to be significantly increased. No significant differences were found in TGs (p=0.19), ESR (p=0.02), CRP (p=0.39), conjugated bilirubin (p=0.28) and unconjugated bilirubin (p=0.78), serum creatinine (p=0.27), HOMA%B (p=0.67), body weight (p=0.06), IGF-1 (p=0.019) and HDL (p=0.0167).

[0189] Between-group analysis

[0190] Intergroup analysis showed that, compared with the control diet, after six FMD cycles, participants in the FMD→control group exhibited significantly lower levels of serum leptin (p<0.001), insulin (p<0.001), glucose (p=0.007), total cholesterol (p=0.002), low-density lipoprotein (p=0.014), CRP (p=0.005), AST (p=0.002), ALT (p=0.001), and HOMAIR (p<0.001) levels, and increased serum levels of hunger hormones (p<0.001) and HOMA%S (p<0.001). A decreasing trend was observed in the levels of IGF-1 (p = 0.029) and ESR (p = 0.017), but no significant differences were found in the levels of HDL (p = 0.2), TGs (p = 0.07), conjugated bilirubin (p = 0.18), unconjugated bilirubin (p = 0.74), urea (p = 0.35), serum creatinine (p = 0.17), and HOMA%B (p = 0.039).

[0191] Participants in the FMD → control group showed significantly lower WC (p<0.001), body weight (p<0.001), BMI (p<0.001), and estimated FM (% and Kg, both p<0.001) and higher estimated MM (% and Kg, both p<0.001), while only VF level showed a decreasing trend (p=0.02) (Table 4).

[0192] During the second 6-month period, participants in the control → FMD group received FMD intervention, while participants in the FMD → control group followed their dietary habits and did not undergo FMD. At the end of the period, participants in the control → FMD group had significantly lower LDL, serum glucose, and urea levels compared to the FMD → control group (p < 0.001, p = 0.01, and p = 0.01, respectively). A decreasing trend in IGF-1 levels was observed (p = 0.02), but lower levels were observed in high-density lipoprotein (p = 0.02), leptin (p = 0.23), ghrelin (p = 0.13), insulin (p = 0.48), total cholesterol (p = 0.08), TGs (p = 0.63), ESR (p = 0.12), CPR (p = 0.48), conjugated bilirubin (p = 0.81) and unconjugated bilirubin (p = 0.7), AST (p = 0.63), ALT (p = 0.41), and... No significant differences were observed in serum creatinine (p = 0.96), HOMA%B (p = 0.018), HOMA%S (p = 0.92), and HOMAIR (p = 0.48). No significant differences were also observed in WC (p = 0.26), body weight (p = 0.18), BMI (p = 0.55), and estimated FM (% and Kg, p = 0.7 and p = 0.62, respectively), MM (% and Kg, p = 0.06 and p = 0.03, respectively), and VF level (p = 0.3) (Table 4).

[0193] discuss

[0194] This disclosure demonstrates that, after a FMD cycle, taste and olfactory sensitivity significantly improved in both between-group and within-group analyses (Tables 3 and 4, Figure 2). Figure 3 , Figure 4 When compared with the control group, OT, OI, TDI, sweetness, and TTS were the main outcome variables that showed significant improvements in FMD→control after the 6-month FMD period. Similar results were observed in control→FMD after the crossover experiment and 6 cycles of FMD (Table 3). Notably, the proportion of patients with hyposmia was reduced by nearly 6-fold, and the FMD cycle had a long-term effect on taste and olfactory sensitivity (Table 3, Figure 2).

[0195] It is worth noting that the many improvements maintained 6 months after the end of the FMD cycle increase the likelihood that the FMD cycle will be at least partially effective if it is repeated regularly throughout the year, possibly every 3-4 months, while making this approach more feasible by requiring only 15-20 days of dietary changes per year.

[0196] Furthermore, after a 6-month follow-up, the levels of hunger hormone, leptin, and insulin in the FMD→control group remained significantly different from baseline.

[0197] In addition, these results provide strong evidence for the ability of FMD cycles to improve taste and smell, while also reducing many risk factors for cardiometabolic diseases, reductions that are not solely due to weight loss.

[0198] FMD cycles also reduced metabolic and inflammatory markers and decreased medication use in patients with diabetes, with most chemoreceptor and metabolic changes unrelated to weight loss. In summary, this disclosure provides evidence that cyclic FMD improves chemoreceptor function and reduces cardiovascular metabolic risk factors without requiring long-term lifestyle modifications.

[0199] References

[0200] 1. Berthoud, HR, and Zheng, H. (2012). Modulation of taste responsiveness and food preference by obesity and weight loss. Physiol Behav107,527-532.10.1016 / j.physbeh.2012.04.004.

[0201] 2.Peng, M., Coutts, D., Wang, T., and Cakmak, YO (2019). Systematic review of olfactory shifts related to obesity. Obes Rev 20, 325-338.10.1111 / obr.12800.

[0202] 3. Micarelli, A., Malacrida, S., Strapazzon, G., Mrakic-Sposta, S., Micarelli, B., Alessandrini, N., Carbini, V., Caputo, S., Falla, M., and Alessandrini, M. (2021). Impact of Nutritional Intervention on Taste Perception-AScoping Review.Foods10.10.3390 / foods10112747.

[0203] 4. Poessel, M., Breuer, N., Joshi, A., Pampel, A., Villringer, A., Hummel, T., and Horstmann, A. (2020). Reduced Olfactory Bulb Volume in Obesity and Its Relation to Metabolic Health Status. Front Hum Neurosci 14, 586998. 10.3389 / fnhum.2020.586998.

[0204] 5. Micarelli, A., Vezzoli, A., Malacrida, S., Micarelli, B., Misici, I., Carbini, V., Iennaco, I., Caputo, S., Mrakic-Sposta, S., and d'Alessandrini, M. (2023). Taste Function in Adult Humans from Lean Condition to Stage II Obesity: Interactions with Biochemical Regulators, Dietary Habits, and Clinical Aspects. Nutrients 15. 10.3390 / nu15051114.

[0205] 6. Makaronidis, J.M., Neilson, S., Cheung, W.H., Tymoszuk, U., Pucci, A., Finer, N., Doyle, J., Hashemi, M., Elkalaawy, M., Adamo, M., et al. (2016). Reported appetite, taste and smell changes following Roux-en-Y gastric bypass and sleeve gastrectomy: Effect of gender, type 2 diabetes and relationship to post-operative weight loss. Appetite 107, 93-105. 10.1016 / j.appet.2016.07.029.

[0206] 7. Micarelli, A., Mrakic-Sposta, S., Micarelli, B., Malacrida, S., Misici, I., Carbini, V., Iennaco, I., Caputo, S., Vezzoli, A., and Alessandrini, M. (2022). Smell Impairment in Stage I-II Obesity: Correlation with Biochemical Regulators and Clinical Aspects. Laryngoscope 132, 2028-2035. 10.1002 / lary.30325.

[0207] 8. Velluzzi, F., Deledda, A., Onida, M., Loviselli, A., Crnjar, R., and Sollai, G. (2022). Relationship between Olfactory Function and BMI in Normal Weight Healthy Subjects and Patients with Overweight or Obesity. Nutrients 14. 10.3390 / nu14061262.

[0208] 9. Espinoza García AS, Martínez Moreno AG, Reyes Castillo Z. The role of ghrelin and leptin in feeding behavior: genetic and molecular evidence. Endocrinología, Diabetes y Nutrición (English version). 2021;68(9):654-663. doi:10.1016 / j.endien.2020.10.009

[0209] 10. Longo, V. D., and Panda, S. (2016). Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab 23, 1048-1059. 10.1016 / j.cmet.2016.06.001. <11. Brandhorst, S. (2021). Fasting and fasting-mimicking diets for chemotherapy augmentation. Geroscience 43, 1201-1216. 10.1007 / s11357-020-00317-7.

[0211] 12. Wei, M., Brandhorst, S., Shelehchi, M., Mirzaei, H., Cheng, C. W., Budniak, J., Groshen, S., Mack, W. J., Guen, E., Di Biase, S., et al. (2017). Fasting-mimicking diet and markers / risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med 9. 10.1126 / scitranslmed.aai8700.

[0212] 13. Sulaj, A., Kopf, S., von Rauchhaupt, E., Kliemank, E., Brune, M., Kender, Z., Bartl, H., Cortizo, F. G., Klepac, K., Han, Z., et al. (2022). Six-Month Periodic Fasting in Patients With Type 2 Diabetes and Diabetic Nephropathy: A Proof-of-Concept Study. J Clin Endocrinol Metab 107, 2167-2181. 10.1210 / clinem / dgac197.

[0213] 14. Vignini, A., Borroni, F., Sabbatinelli, J., Pugnaloni, S., Alia, S., Taus, M., Ferrante, L., Mazzanti, L., and Fabri, M. (2019). General Decrease of Taste Sensitivity Is Related to Increase of BMI: A Simple Method to Monitor Eating Behavior. Dis Markers 2019, 2978026. 10.1155 / 2019 / 2978026.

[0214] 15. Landis, B. N., Welge-Luessen, A., A., Bende, M., Mueller, C. A., Nordin, S., and Hummel, T. (2009). "Taste Strips" - a rapid, lateralized, gustatory bedside identification test based on impregnated filter papers. J Neurol 256, 242 - 248. 10.1007 / s00415-009-0088-y.

[0215] 16. Maloh, J., Wei, M., Hsu, W. C., Caputo, S., Afzal, N., and Sivamani, R. K. (2023). The Effects of a Fasting Mimicking Diet on Skin Hydration, Skin Texture, and Skin Assessment: A Randomized Controlled Trial. J Clin Med 12. 10.3390 / jcm12051710.

[0216] 17. Hummel, T., Kobal, G., Gudziol, H., and Mackay-Sim, A. (2007). Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol 264, 237-243. 10.1007 / s00405-006-0173-0.

[0217] 18. Hummel, T., Sekinger, B., Wolf, S.R., Pauli, E., and Kobal, G. (1997). 'Sniffin' sticks': olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 22, 39-52. 10.1093 / chemse / 22.1.39.

[0218] 19. Hedner, M., Larsson, M., Arnold, N., Zucco, G.M., and Hummel, T. (2010). Cognitive factors in odor detection, odor discrimination, and odor identification tasks. J Clin Exp Neuropsychol 32, 1062-1067. 10.1080 / 13803391003683070.

[0219] 20. Rumeau, C., Nguyen, D.T., and Jankowski, R. (2016). How to assess olfactory performance with the Sniffin' Sticks Eur Ann Otorhinolaryngol Head Neck Dis 133, 203 - 206. 10.1016 / j.anorl.2015.08.004.

[0220] 21. Campolo, J., Corradi, E., Rizzardi, A., Parolini, M., Dellanoce, C., Di Guglielmo, M. L., Tarlarini, P., Cattaneo, M., Trivella, M. G., and De Maria, R. (2021). Correlates of olfactory impairment in middle - aged non - diabetic Caucasian subjects with stage I - II obesity. Eur Arch Otorhinolaryngol 278, 2047 - 2054. 10.1007 / s00405 - 020 - 06442 - 5.

[0221] 22. Oleszkiewicz, A., Schriever, V. A., Croy, I., A., and Hummel, T. (2019). Updated Sniffin'Sticks normative data based on an extended sample of 9139 subjects. Eur Arch Otorhinolaryngol 276, 719 - 728. 10.1007 / s00405 - 018 - 5248 - 1.

[0222] 23. Mueller, C., Kallert, S., Renner, B., Stiassny, K., Temmel, A. F., Hummel, T., and Kobal, G. (2003). Quantitative assessment of gustatory function in a clinical context using impregnated "taste strips". Rhinology 41, 2 - 6.

[0223] 24. Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., and Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412 - 419. 10.1007 / bf00280883.

[0224] 25. Poessel, M., Morys, F., Breuer, N., Villringer, A., Hummel, T., and Horstmann, A. (2022). Brain response to food odors is not associated with body mass index and obesity-related metabolic health measures. Appetite 168, 105774. 10.1016 / j.appet.2021.105774.

[0225] 26. Aandstad, A., Holtberget, K., Hageberg, R., Holme, I., and Anderssen, S. A. (2014). Validity and reliability of bioelectrical impedance analysis and skinfold thickness in predicting body fat in military personnel. Mil Med 179, 208 - 217. 10.7205 / milmed-d-12-00545.

[0226] 27. Betts, J.A., Smith, H.A., Johnson-Bonson, D.A., Ellis, T.I., Dagnall, J., Hengist, A., Carroll, H., Thompson, D., Gonzalez, J.T., and Afman, G.H. (2019). The Energy Cost of Sitting versus Standing Naturally in Man. Med Sci Sports Exerc 51, 726 - 733. 10.1249 / mss.0000000000001841.

[0227] 28. Pasanta, D., Htun, K.T., Pan, J., Tungjai, M., Kaewjaeng, S., Chancharunee, S., Tima, S., Kim, H.J., J., and Kothan, S. (2021). Waist Circumference and BMI Are Strongly Correlated with MRI-Derived Fat Compartments in Young Adults. Life (Basel) 11. 10.3390 / life11070643.

[0228] 29. Wise, P.M., Nattress, L., Flammer, L.J., and Beauchamp, G.K. (2016). Reduced dietary intake of simple sugars alters perceived sweet taste intensity but not perceived pleasantness. Am J Clin Nutr 103, 50 - 60. 10.3945 / ajcn.115.112300.

[0229] 30. Cattaneo, C., Mambrini, S. P., Gilardini, L., Scacchi, M., Pagliarini, E., and Bertoli, S. (2023). Impact of 4-week of a restricted Mediterranean diet on taste perception, anthropometric, and blood parameters in subjects with severe obesity. Front Nutr 10, 1196157. 10.3389 / fnut.2023.1196157.

Claims

1. A dietary composition for the prevention and / or treatment of olfactory and / or gustatory hypoolfaction in human subjects, said dietary composition comprising: A fasting-mimicking diet component, taken during a first time period, provides less than 50% of the subject's normal calorie intake while restricting protein and sugar; as well as The subject then took a second dietary component, which provided 60-100% of their normal calorie intake. The simulated fasting diet components and the refeeding diet components are taken over multiple cycles.

2. The dietary composition according to claim 1, wherein, The dietary composition was administered to human subjects with a body mass index (BMI) ≥ 25, preferably, the BMI being equal to or greater than 25 and less than 40.

3. The dietary composition according to claim 1 or 2, wherein, The first time period is 2 to 10 days, preferably 2 to 6 days, more preferably 5 days, and / or the second time period is 7 to 85 days, preferably 25 to 26 days.

4. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet components and the refeeding diet components are taken over multiple cycles for at least 6 months, preferably 6-12 months.

5. The dietary composition according to claim 1 or 2, wherein, When compared with the blood concentrations of leptin and / or ghrelin measured before starting to take the dietary composition, the blood concentration of leptin measured 6 months after starting to take the dietary composition decreased by 5 to 18 ng / ml and / or the blood concentration of ghrelin increased by 30 to 90 pg / ml.

6. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet provides the subject with no more than 1200 kcal / day, preferably 600-1100 kcal / day.

7. The dietary composition according to claim 6, wherein, The first time period is 5 days, and the simulated fasting diet provides the subject with 800-1200 kcal / day on the first day of the first time period, and 600-800 kcal / day from the second to the fifth day of the first time period.

8. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet consists of a protein content of less than or equal to 36g / day provided to the subject, preferably 0-20g / day.

9. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet provides the subject with no more than 11 kcal / kg (body weight) / day, preferably 2-5 kcal / kg (body weight) / day.

10. The dietary composition according to claim 1 or 2, wherein, The protein content of the simulated fasting diet components is less than 15% of the total calories provided by the simulated fasting diet components, preferably less than 12%.

11. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet components include sugars that account for less than 50% of the total calories provided by the simulated fasting diet components, preferably less than 48%.

12. The dietary composition according to claim 1 or 2, wherein, The fat content of the simulated fasting diet components is equal to or greater than 40% of the total calories provided by the simulated fasting diet components, preferably less than 50%, and more preferably less than 48%.

13. The dietary composition according to claim 1 or 2, wherein, The simulated fasting diet consists of at least 45% calories from fatty acids, up to 5% calories from plant-based protein, and up to 50% calories from carbohydrates.

14. A dietary composition for the prevention and / or treatment of diseases or disorders or conditions of leptin and / or ghrelin imbalance in human subjects, said dietary composition comprising: A fasting-mimicking diet component, taken during a first time period, provides less than 50% of the subject's normal calorie intake while restricting protein and sugar; as well as The re-eating diet component, taken at a second time interval, provides the subject with 60-100% of their normal calorie intake. The simulated fasting diet components and the refeeding diet components are taken over multiple cycles.

15. The dietary composition according to claim 14, wherein, The disease, disorder, or symptom mentioned is selected from overweight or obesity.

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