Composite probiotic and use thereof in the preparation of a product for improving mild cognitive impairment

Abstract

Disclosed are a composite probiotic and application thereof in preparation of a product for improving mild cognitive impairment, which can effectively relieve cognitive conditions of the elderly with mild cognitive impairment and improve the depression and anxiety of the elderly with mild cognitive impairment. The composite probiotic comprises Lactobacillus plantarum Lp115, Lactobacillus acidophilus NCFM, Bifidobacterium lactis HN019, Paracasei Lpc37, Lactobacillus acidophilus La14, Bifidobacterium bifidum Bb06, Lactobacillus rhamnosus HN001, Bifidobacterium lactis Bl04, Bifidobacterium lactis Bi07 and Bifidobacterium longum Bl05.

Description

Technical Field

[0001] This invention relates to the technical field of medicine, and more particularly to a compound probiotic and its application in the preparation of products for improving mild cognitive impairment. Background Technology

[0002] Population aging is a widespread phenomenon globally, and the rate of aging in China is accelerating. According to surveys, by the end of 2024, my country's population aged 60 and above would reach 310.31 million, accounting for 22.0% of the total population. With increasing age, the incidence of many age-related chronic diseases, such as cognitive decline, is rising annually. The number of people with dementia in my country is approximately one-quarter of the global total, which not only affects the quality of life of individuals and their families but also places a heavy economic burden on the healthcare system. Since there is currently no effective treatment for dementia, early intervention is the most effective way to prevent it.

[0003] Mild cognitive impairment (MCI) is a cognitive state that falls between normal aging and dementia. The prevalence of MCI among people aged 65 and older in China is approximately 20.8%. In 2018, the American Academy of Neurology updated its guidelines for the diagnosis and treatment of MCI, recommending that reversible risk factors be considered for MCI patients, and suggesting methods such as enhanced cognitive training to slow cognitive decline. The guidelines also specifically emphasize the importance of research on the role of gut microbiota in the MCI population.

[0004] The gut microbiota is a dynamic ecosystem influenced by a variety of factors, including genetics, diet, metabolism, age, geographical environment, and antibiotic treatment. Recent evidence suggests a clear link between changes in the gut microbiota and cognitive behavior. Furthermore, based on animal and clinical studies, the "microbe-gut-brain axis" theory has been proposed, illustrating the significant impact of the gut microbiota on human brain health and cognitive function. Additionally, the slogan "food is medicine" and the theme of "integrating food and nutrition into healthcare" have recently gained popularity. Clinical research results indicate that specific dietary patterns or nutrients play a protective role in cognitive function, such as enhancing memory, executive function, improving attention, and protecting neurons. Therefore, providing an intervention product that combines probiotics and specific dietary patterns to improve cognitive-related problems in older adults with mild cognitive impairment is highly meaningful. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the technical problem to be solved by the present invention is to provide a compound probiotic that can effectively alleviate the cognitive status of elderly people with mild cognitive impairment and improve their depressive and anxious mood.

[0006] The technical solution of this invention is: this compound probiotic includes: Lactobacillus plantarum Lp115, Lactobacillus acidophilus NCFM, Bifidobacterium lactis HN019, Lactobacillus paracasei Lpc37, Lactobacillus acidophilus La14, Bifidobacterium bifidum Bb06, Lactobacillus rhamnosus HN001, Bifidobacterium lactis Bl04, Bifidobacterium lactis Bi07, and Bifidobacterium longum Bl05.

[0007] The beneficial effects of this invention are: it can effectively alleviate the cognitive status of elderly people with mild cognitive impairment and improve their depressive and anxious moods.

[0008] The application of this compound probiotic in the preparation of products that improve mild cognitive impairment is also provided. Attached Figure Description

[0009] Figure 1 This is a line graph showing the change in MMSE scores from baseline;

[0010] Figure 2 This is a line graph showing the change in MoCA score from baseline;

[0011] Figure 3 This is a line graph showing the change in ADAS-cog score from baseline;

[0012] Figure 4 This is a line graph showing the change in ADL scores from baseline;

[0013] Figure 5 This is a line graph showing the change in HAMD scores from the baseline;

[0014] Figure 6 This is a line graph showing the change in HAMA score from baseline.

[0015] Where ns represents P≥0.05, * represents P<0.05, ** represents P<0.01, and *** represents P<0.001. Detailed Implementation

[0016] This compound probiotic includes: Lactobacillus plantarum Lp115, Lactobacillus acidophilus NCFM, Bifidobacterium lactis HN019, Lactobacillus paracasei Lpc37, Lactobacillus acidophilus La14, Bifidobacterium bifidum Bb06, Lactobacillus rhamnosus HN001, Bifidobacterium lactis Bl04, Bifidobacterium lactis Bi07, and Bifidobacterium longum Bl05.

[0017] The beneficial effects of this invention are: it can effectively alleviate the cognitive status of elderly people with mild cognitive impairment and improve their depressive and anxious moods.

[0018] Preferably, the compound probiotics are composed of 1×10⁻⁶ by weight. 9~10 10 CFU / g Lactobacillus plantarum Lp115, 1×10 9 ~10 10 CFU / g Lactobacillus acidophilus NCFM, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis HN019, 1×10 9 ~10 10 CFU / g Lactobacillus paracasei Lpc37, 1×10 9 ~10 10 CFU / g Lactobacillus acidophilus La14, 1×10 9 ~10 10 CFU / g Bifidobacterium bifidum Bb06, 1×10 9 ~10 10 CFU / g Lactobacillus rhamnosus HN001, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis B104, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis Bi07 and 1×10 9 ~10 10 CFU / g Bifidobacterium longum Bl05.

[0019] Preferably, the compound probiotics and the anti-inflammatory diet together form a compound probiotics and anti-inflammatory diet synergistic intervention package, wherein the anti-inflammatory diet includes the following daily intake: dark green leafy vegetables ≥200g, deep-sea fish ≥50g, soy products ≥30g, nuts ≥20g, and red meat ≤70g.

[0020] Preferably, the viable bacteria content in the synergistic intervention package is greater than or equal to 4 × 10⁻⁶. 10 CFU / g.

[0021] Preferably, the synergistic intervention package includes food, health products, or medically acceptable carriers, excipients, or additives.

[0022] Preferably, the synergistic intervention package includes prebiotics.

[0023] Preferably, the dosage form of the compound probiotic is capsules, tablets, granules, or powder.

[0024] The application of this compound probiotic in the preparation of products that improve mild cognitive impairment is also provided.

[0025] Preferably, this compound probiotic is used in the preparation of products that improve cognitive function and symptoms of depression and anxiety in the elderly.

[0026] The embodiments of the present invention will be described in detail below.

[0027] The combination of probiotics in the synergistic intervention package involved in the following embodiments is as follows:

[0028] 4×10 9 CFU / g Lactobacillus plantarum Lp115, 4×10 9 CFU / g Lactobacillus acidophilus NCFM, 4×10 9 CFU / g Bifidobacterium lactis HN019, 4×10 9 CFU / g Lactobacillus paracasei Lpc37, 4×10 9 CFU / g Lactobacillus acidophilus La14, 4×10 9 CFU / g Bifidobacterium bifidum Bb06, 4×10 9 CFU / g Lactobacillus rhamnosus HN001, 4×10 9 CFU / g Bifidobacterium lactis B104, 4×10 9 CFU / g Bifidobacterium lactis Bi07 and 4×10 9 CFU / g Bifidobacterium longum Bl05.

[0029] The experimental results were statistically analyzed using R. Compared with the control group, P < 0.05 indicated a significant difference in the results.

[0030] Example

[0031] To investigate the effect of the synergistic intervention package on elderly patients with mild cognitive impairment, this embodiment conducted a randomized controlled clinical trial to intervene with the synergistic intervention package in elderly patients with mild cognitive impairment.

[0032] This trial was conducted in accordance with the guidelines of the International Coordinating Committee and the ethical principles of the Declaration of Helsinki. The trial was reviewed and approved by the Ethics Review Committee of the China-Japan Friendship Hospital (Ethics Review No.: 2023-KY-227) and registered with the Chinese Clinical Trial Registry (Registration No.: ChiCTR2300079015). All research participants who agreed to participate in this study signed written informed consent forms.

[0033] Participants in this trial met the following criteria:

[0034] (1) Age 60 years or older;

[0035] (2) The patient or a person in the know reports, or an experienced clinician discovers cognitive impairment;

[0036] (3) Based on cognitive tests, there is objective evidence of impairment in one or more cognitive functional domains, with a Mini-Mental State Examination (MMSE) score ≤26 and / or a Montreal Cognitive Assessment Scale (MoCA) score ≤26.

[0037] (4) Maintain independent general daily living skills, with an Activity of Daily Living Scale (ADL) score ≤ 26;

[0038] (5) The diagnostic criteria for dementia have not yet been met.

[0039] Furthermore, none of the participants in this experiment had the following conditions:

[0040] (1) Cognitive impairment caused by other neurological diseases or other reasons such as syphilis, alcoholic encephalopathy, etc.

[0041] (2) History of mental illness such as schizophrenia or bipolar disorder;

[0042] (3) Those with poor compliance, physical condition, or educational level that do not allow them to complete the examination;

[0043] (4) Those who have consumed products containing probiotics in the past two months, or those who have had infectious diseases or used antibiotics or hormone drugs;

[0044] (5) History of organic intestinal lesions or major intestinal surgery;

[0045] (6) Other situations that may interfere with this test.

[0046] This trial aimed to recruit 60 elderly patients with mild cognitive impairment, and actually recruited 60 elderly patients with mild cognitive impairment, all from the China-Japan Friendship Hospital in Beijing. A total of 58 patients completed the trial.

[0047] Eligible study participants were enrolled after signing informed consent forms and were randomly assigned to either the intervention or control group. Clinical study participants were aware of their assigned group, but those who performed the cognitive assessments were unaware of the group assignments and related safety evaluations.

[0048] Enrolled participants underwent cognitive assessments using cognitive scales, including the MMSE, MoCA, and the Alzheimer's Disease Rating Scale-Cognitive Scale (ADAS-cog); depression and anxiety assessments using the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA); Activities of Daily Living (ADL) assessments; a 24-hour dietary recall study to track food intake for three consecutive days and calculate the Dietary Inflammatory Index (DII) score; and a System Inflammation Response Index (SIRI) based on complete blood count results. Demographic information, disease status, and medication use were also recorded.

[0049] The intervention was maintained for 24 weeks, during which time patients could take compound probiotics daily or not take any probiotics or related products, with a daily dosage of 4 x 10. 10 CFU. During the intervention, the intervention group also needed to follow an anti-inflammatory diet as instructed, increasing the intake of dark green leafy vegetables, deep-sea fish, soy products, and nuts, and reducing the intake of red meat, processed meat, refined grains, sweets, and fried foods, including daily intake of: dark green leafy vegetables ≥200g, deep-sea fish ≥50g, soy products ≥30g, nuts ≥20g, and red meat ≤70g. At 12 weeks of intervention, participants were again tested on cognitive scales, depression and anxiety tests, and daily living skills tests, including MMSE, MoCA, ADAS-cog, HAMD, HAMA, and ADL. At the end of the intervention, participants were again assessed on MMSE, MoCA, ADAS-cog, HAMD, HAMA, and ADL, and DII and SIRI scores were calculated to assess the effectiveness of the anti-inflammatory diet and improvements in cognition, mood, and daily living skills.

[0050] To investigate the effects of the synergistic intervention package on elderly patients with mild cognitive impairment, a randomized controlled clinical trial was conducted. A total of 60 eligible participants were randomly assigned to either the intervention or control group (30 participants in each group), and 58 participants completed the trial. There were no significant differences between the two groups in demographic characteristics, ApoEε4 carrier status, MMSE, MoCA, ADAS-cog, and ADL scores (Table 1), demonstrating homogeneity and comparability between the groups.

[0051] Table 1 Baseline characteristics of study participants

[0052] intervention group control group P gender male 11(36.7％) 12(40.0％) 0.999 female 19(63.3％) 18(60.0％) age 73.6±7.9 71.3±6.5 0.218 Years of education 12.3±4.2 12.0±3.8 0.807 ApoEε4 carries Not carried 9(47.4％) 16(69.6％) 0.209 carry 10(52.6％) 7(30.4％) Heterozygote 10(100％) 6(85.7％) 0.412 homozygote 0(0％) 1(14.3％) MMSE 23.3±3.2 24.5±3.1 0.154 MoCA 17.8±4.7 18.6±3.8 0.497 ADAS-cog 15.793±9.599 13.178±5.658 0.213 ADL 21.6±2.2 21.1±1.6 0.263

[0053] Note: MMSE: Mini-Mental State Examination, MoCA: Montreal Cognitive Assessment Scale, ADAS-cog: Alzheimer's Disease Assessment Scale - Cognitive Section, ADL: Activities of Daily Living Scale. For categorical variables, all data are expressed as number of cases (percentage) [n(%)]; for continuous variables, they are expressed as mean ± standard deviation.

[0054] 1. The effect of the synergistic intervention package on DII and SIRI in elderly patients with mild cognitive impairment.

[0055] After the intervention, both the DII and SIRI scores in the intervention group decreased compared to baseline (Table 2). The DII and SIRI scores in the placebo group showed no significant difference from baseline. This indicates that the synergistic intervention package has a significant effect on improving the systemic inflammatory state in elderly patients with mild cognitive impairment.

[0056] Table 2 Changes in DII and SIRI scores at baseline and after intervention.

[0057]

[0058] Note: For independent samples t-tests (after logarithmic transformation), data are presented as medians (25th and 75th percentiles); * indicates P < 0.05.

[0059] 2. The effect of the collaborative intervention package on the cognitive function of elderly patients with mild cognitive impairment.

[0060] The adjusted mean change in MMSE score from baseline at 12 weeks was 0.05 in the intervention group and -0.96 in the control group (difference 1.02; 95% CI, -0.02 to 2.05; P = 0.055; Table 3). Figure 1 At this point, there were differences in scores, but they were not significant. The adjusted mean change in MMSE score relative to baseline at week 24 was -0.25 in the intervention group and -1.93 in the control group (difference 1.68; 95% CI, 0.63 to 2.72; P = 0.002; Table 3). Figure 1 This indicates that after 24 weeks of intervention, the synergistic intervention package significantly alleviated the decrease in MMSE scores in the intervention group.

[0061] Changes in ADAS-cog and MoCA also showed similar trends (Table 3). Figure 2-3 At week 12 of the intervention, a difference was observed in the scale scores between the intervention group and the control group, but it was not statistically significant. At week 24 of the intervention, the decrease in scale scores in the intervention group was significantly smaller than that in the control group, indicating that the cognitive-related functional decline had been alleviated.

[0062] There were no significant differences in ADL scores between the intervention group and the control group before and after the intervention (Table 3). Figure 4This indicates that it has no significant impact on daily living abilities.

[0063] Table 3. Differences in changes of cognitive-related indicators from baseline.

[0064]

[0065] Note: MMSE: Mini-Mental State Examination, MoCA: Montreal Cognitive Assessment Scale, ADAS-cog: Alzheimer's Disease Assessment Scale - Cognitive Component, ADL: Activities of Daily Living Scale.

[0066] 3. The effect of the collaborative intervention package on anxiety and depression symptoms in elderly patients with mild cognitive impairment.

[0067] After the intervention, the HAMD and HAMA scores in the intervention group were significantly lower than at baseline (Table 4). Figure 5-6 The HAMD and HAMA scores in the placebo group showed no significant difference from baseline. The intervention group showed a significant difference compared to the control group, indicating that the synergistic intervention package had a significant effect on improving depression and anxiety in elderly patients with mild cognitive impairment.

[0068] Table 4. Differences in the changes of anxiety and depression indicators from baseline.

[0069]

[0070] Note: HAMD: Hamilton Depression Rating Scale, HAMA: Hamilton Anxiety Rating Scale.

[0071] Based on the above experiments, it has been demonstrated that the synergistic intervention package of the present invention can effectively alleviate the inflammatory state, cognitive function, and depressive and anxiety symptoms in elderly patients with mild cognitive impairment.

[0072] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A compound probiotic, characterized in that: It includes: Lactobacillus plantarum Lp115, Lactobacillus acidophilus NCFM, Bifidobacterium lactis HN019, Lactobacillus paracasei Lpc37, Lactobacillus acidophilus La14, Bifidobacterium bifidum Bb06, Lactobacillus rhamnosus HN001, Bifidobacterium lactis Bl04, Bifidobacterium lactis Bi07, and Bifidobacterium longum Bl05.

2. The compound probiotic according to claim 1, characterized in that: The compound probiotics are formulated in the following proportions by weight: 1×10 9 ~10 10 CFU / g Lactobacillus plantarum Lp115, 1×10 9 ~10 10 CFU / g Lactobacillus acidophilus NCFM, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis HN019, 1×10 9 ~10 10 CFU / g Lactobacillus paracasei Lpc37, 1×10 9 ~10 10 CFU / g Lactobacillus acidophilus La14, 1×10 9 ~10 10 CFU / g Bifidobacterium bifidum Bb06 1×10 9 ~10 10 CFU / g Lactobacillus rhamnosus HN001, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis B104, 1×10 9 ~10 10 CFU / g Bifidobacterium lactis Bi07 and 1×10 9 ~10 10 CFU / g Bifidobacterium longum Bl05.

3. The compound probiotic according to claim 2, characterized in that: Together with an anti-inflammatory diet, it forms a compound probiotic and anti-inflammatory diet synergistic intervention package. The anti-inflammatory diet includes the following daily intake: dark green leafy vegetables ≥200g, deep-sea fish ≥50g, soy products ≥30g, nuts ≥20g, and red meat ≤70g.

4. The compound probiotic according to claim 3, characterized in that: The viable bacteria content in the synergistic intervention package is greater than or equal to 4 × 10⁻⁶. 10 CFU / g.

5. The compound probiotic according to claim 2, characterized in that: The synergistic intervention package includes food, health products, or medically acceptable carriers, excipients, or additives.

6. The compound probiotic according to claim 5, characterized in that: The synergistic intervention package includes prebiotics.

7. The compound probiotic according to claim 6, characterized in that: The compound probiotics are available in capsule, tablet, granule, or powder form.

8. The application of the compound probiotics according to claim 1 in the preparation of products for improving mild cognitive impairment.

9. The application of the compound probiotics according to claim 8 in the preparation of products for improving mild cognitive impairment, characterized in that: Its application is in the preparation of products that improve cognitive function and symptoms of depression and anxiety in the elderly.

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