CN115590889A - Bifidobacterium breve for regulating biological circadian rhythm and application thereof - Google Patents
Bifidobacterium breve for regulating biological circadian rhythm and application thereof Download PDFInfo
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- CN115590889A CN115590889A CN202211241754.7A CN202211241754A CN115590889A CN 115590889 A CN115590889 A CN 115590889A CN 202211241754 A CN202211241754 A CN 202211241754A CN 115590889 A CN115590889 A CN 115590889A
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Abstract
The invention discloses bifidobacterium breve for regulating biological circadian rhythm and application thereof, belonging to the technical field of microorganisms. The bifidobacterium breve CCFM1025 intervention is given to sleep-deprived animals, so that the normal expression of circadian rhythm related genes in the brain can be effectively recovered, the serotonin turnover rate and the melatonin content in the brain are improved, and the defects of cognitive behaviors and memory behaviors are alleviated. In addition, CCFM1025 intervention can improve intestinal flora and restore normal synthesis of flora metabolites such as S-adenosylmethionine, gamma-aminobutyric acid, isovaleric acid and the like which are beneficial to sleep, cognition and memory. The invention expands the application range of the bifidobacterium breve as the probiotics and has very important significance for deeply excavating the functions of the probiotics and developing the probiotics with higher health care value.
Description
Technical Field
The invention relates to bifidobacterium breve for regulating biological circadian rhythm and application thereof, belonging to the technical field of microorganisms.
Background
Sleep disorders are a very common disease that disrupts the normal circadian rhythm, thereby having a negative impact on mental and physical health. Long-term circadian rhythm disorders can lead to a variety of complications, such as depression, alzheimer's disease, cardiovascular diseases, and the like. Circadian rhythm disturbances have a number of negative effects on brain function, with impairment of cognitive and memory functions being a major feature. Research shows that sleep deprivation causes damage to various high-order cognitive processes of a human body, such as decision making, time memory, divergent thinking, problem solving, error detection and other processes; its mechanism is associated with neurophysiological changes in the prefrontal cortex. On the contrary, a large number of researches show that the visual plot recognition and memory capacity can be enhanced by sleeping after learning.
Recent studies have found that there is a strong correlation between disorders of the intestinal flora and disorders of circadian rhythm. Studies have shown that circadian rhythm disturbances, which are caused by sleep disruption, can significantly alter the intestinal flora composition of mice. The continuous broad-spectrum antibiotic treatment can obviously reduce the time of non-rapid eye movement sleep of the mice while depriving the intestinal flora of the mice, and the phenomenon has obvious correlation with the abnormal metabolism of amino acid and vitamin of the intestinal flora. In clinical research, the diversity of intestinal flora, the abundance of anaerobes and short-chain fatty acid producing bacteria of insomnia patients are obviously lower than that of healthy people, and the content of propionic acid produced by the intestinal flora and the sleep time have obvious positive correlation. Although the evidence reported above fails to demonstrate a causal relationship between insomnia and gut flora composition, it is undeniable that gut flora may be an important target involved in regulating circadian rhythms.
Thanks to the discovery of the "flora-gut-brain axis" theory, it has also become possible to modulate brain function by modulating gut flora. The gut flora is in signal communication with the brain in a variety of ways, including via the vagus nerve, the immune system, the endocrine system, etc. Metabolites of the intestinal flora have been shown to directly or indirectly affect physiological processes such as neurotransmitter production, blood brain barrier permeability, microglial cell development and the like in the brain, thereby affecting functions such as emotion, cognition, social interaction and the like. Probiotics, an important dietary supplement for regulating the intestinal flora, show great potential in improving nervous system function. Bifidobacteria are the predominant species of bifidobacteria in the intestinal tract of infants and are widely used as probiotics. Bifidobacteria have also been reported to regulate neurophysiological functions, such as antidepressant and Alzheimer's disease reduction in adult individuals. However, the Pharmacological mechanisms of current drugs for the treatment of depression and Alzheimer's disease focus on increasing neurotransmitter content in the brain (e.g., 5-hydroxytryptamine, acetylcholine, etc.), there are no drug strategies that start with regulating circadian mechanisms (Trends in Pharmacological Sciences,2020,41 (7): 434-445 New England Journal of medicine,2019,380 (6): 559-568), and there is no direct evidence that bifidobacteria improve circadian rhythm disturbances caused by sleep deprivation (or insomnia).
Disclosure of Invention
The invention provides application of Bifidobacterium breve (CCFM 1025) in preparing products for regulating biological circadian rhythm, improving cognition and memory impairment caused by insomnia, and regulating intestinal flora disorder and metabolite synthesis abnormality; the bifidobacterium breve CCFM1025 is preserved in Guangdong province microorganism culture collection center in 2018, 6 and 11 months, and the preservation number is GDMCC No.60386, which is disclosed in a patent with the publication number of CN 108949640B.
In one embodiment, the product includes, but is not limited to, a pharmaceutical, a functional food, a fermented food, a nutritional supplement, a food additive, or a functional food.
In one embodiment, the Bifidobacterium breve CCFM1025 is present in the product in an amount of 1 × 10 or more 8 CFU/g or 1X 10 8 CFU/mL。
In one embodiment, the product is a fermented food product produced by fermentation using bifidobacterium breve CCFM1025, the fermented food product comprising a solid food product, a liquid food product, a semi-solid food product.
In one embodiment, the fermented food product comprises a dairy product, a soy product, a fruit and vegetable product; the dairy product comprises milk, sour cream and cheese; the fruit and vegetable products comprise cucumber, carrot, beet, celery and cabbage products.
In one embodiment, the use is for the prevention and/or alleviation of circadian rhythm disorders caused by insomnia.
In one embodiment, the circadian rhythm disorder includes, but is not limited to, abnormal expression of at least one gene of Per1, c-Fos, bdnf in the brain.
In one embodiment, the use further comprises preventing and/or alleviating cognitive and memory impairment caused by insomnia, and increasing the Serotonin (Serotonin) turnover rate and Melatonin (Melatonin) content in the brain.
In one embodiment, the use further comprises restoring disturbances of the intestinal flora resulting from insomnia and abnormal synthesis of metabolites thereof.
In one embodiment, the metabolites include, but are not limited to, abnormal levels of S-adenosyl-methionine, gamma-aminobutyric acid (GABA), and Isovaleric acid (Isovaleric acid).
In one embodiment, the metabolite level change is manifested by an increase in serum gamma-aminobutyric acid and isovaleric acid levels and a decrease in the level of adenosine, the precursor of S-adenosylmethionine.
The invention also claims application of the bifidobacterium breve CCFM1025 in preparing health-care products helpful for improving sleep.
In one embodiment, the content of Bifidobacterium breve CCFM1025 in the health product is more than or equal to 1 x 10 8 CFU/g or 1X 10 8 CFU/mL。
Has the advantages that: the invention provides a new application of bifidobacterium breve CCFM1025 in preventing and/or relieving circadian rhythm disorder caused by insomnia. The intervention of the bifidobacterium breve CCFM1025 given to the sleep deprived mammal can effectively recover the normal expression of circadian rhythm related genes in the brain, improve the serotonin turnover rate and the melatonin content in the brain and relieve the defects of cognitive behaviors and memory behaviors. In addition, CCFM1025 intervention can improve intestinal flora and restore normal synthesis of flora metabolites such as S-adenosylmethionine, gamma-aminobutyric acid and isovaleric acid which are beneficial to sleep, cognition and memory (reflected by increased content of gamma-aminobutyric acid and isovaleric acid and decreased content of adenosine which is a precursor of S-adenosylmethionine in serum). The invention expands the application range of the bifidobacterium breve as the probiotics and also provides theoretical guidance for preventing, relieving and treating the dysfunction of the nervous system by utilizing the probiotics.
Drawings
FIG. 1 is the performance of mice in behavioral experiments; (a) a new object recognition index; (B) a new object discrimination index; wherein P <0.05, P <0.01, P <0.001.
FIG. 2 is a graph of the effect of CCFM1025 on the modulation of serotonin turnover rate and melatonin content abnormalities in the brain of sleep deprived mice; (a) serotonin turnover rate in the mouse nucleus sutureus; (B) melatonin content in mouse nucleus pulposus; wherein P <0.05, P <0.01, P <0.001.
FIG. 3 is a graph showing the effect of CCFM1025 on the regulation of circadian rhythm-associated gene expression in sleep-deprived mice; (A) the expression level of Per1 mRNA in striatum; (B) the expression level of c-Fos mRNA in the striatum; (C) the expression level of bdnf mRNA in the striatum; wherein P <0.05, P <0.01, P <0.001.
FIG. 4 is a graph of the modulating effect of CCFM1025 on the alpha-diversity, beta-diversity of the gut flora in sleep deprived mice; wherein P <0.05, P <0.01.
FIG. 5 is a graph of the effect of CCFM1025 on the regulation of gut flora gene function and its metabolic pathways in sleep deprived mice.
FIG. 6 is a graph of the effect of CCFM1025 on the levels of S-adenosylmethionine precursor (adenosine), gamma-aminobutyric acid and isovaleric acid in serum from sleep deprived mice; wherein P <0.05.
Detailed Description
The bifidobacterium breve CCFM1025 disclosed by the invention is deposited in Guangdong province microbial culture collection center in 2018, 6 and 11, and the deposit number is GDMCC No.60386, which is disclosed in a patent with the publication number of CN 108949640B.
The preparation method of the bifidobacterium breve CCFM1025 bacterial agent comprises the following steps: culturing activated 2-generation Bifidobacterium breve CCFM1025 in MRS liquid culture medium at 37 deg.C for 24 hr, centrifuging at 4 deg.C and 6000 Xg for 3min to collect thallus, discarding supernatant, and resuspending thallus with 10% sterilized and defatted emulsion to reach bacteria concentration of 5X 10 9 CFU/mL。
Example 1: bifidobacterium breve CCFM1025 can improve cognitive and memory behaviors of sleep deprived mice
Selecting 24 male SPF grade C57BL/6J mice, age of the mice is 8-9 weeks, weight is 20 +/-2 g, feeding the mice in an environment with constant room temperature of 22 +/-2 ℃ and humidity of 50 +/-5%, freely eating and drinking water under light/dark cycle of 12 hours, and performing grouping treatment after adapting to 1 week, wherein the grouping treatment period is 1 week. Animal groups and treatment methods are shown in table 1.
TABLE 1 animal experiment grouping and processing method
| Packet name | Daily treatment method |
| Control group (N = 8) | Gavage 200 mu L10% sterilized skim milk |
| Sleep deprivation group (N = 8) | Sleep deprivation + gastric lavage 200 mu L10% sterilized skim milk |
| CCFM1025 intervention group (N = 8) | Sleep deprivation + gavage 200. Mu.L CCFM1025 (5X 10) bacterial agent 9 CFU/mL) |
Sleep deprivation animal models: the sleep deprivation animal model is a widely used animal model for exploring circadian rhythms and sleep disorders. Mouse sleep deprivation models were constructed using the deprived-rod sleep deprivation method, according to which the sleep deprivation group and the CCFM1025 intervention group were treated separately (gavage volume 0.2 mL/day). The method comprises the following steps: deprived rods were swept continuously for 20h from 13. During the period, the squirrel cage is ensured to be dry and tidy, and the mouse can eat and drink water by oneself; the blank control group was not treated at all.
And (3) identifying a new object: in the habituation phase, one test mouse was placed in the field and allowed to explore for 2min. After habituation, two objects of similar size but different shape and colour were placed in opposite corners of the box, 5cm from the side walls, and then a test mouse was placed in the centre of the field and allowed to explore the arena containing the two objects for 5min. After 3h, one object was replaced by another new object, which was similar in size but different in shape and color from the previous object. The same test mice were then placed in the center and allowed to explore the field and two objects for 5min. The time and frequency of the mice's exploration for the new and old objects were recorded. Identification index = new object exploration time/(new object exploration time + familiar object exploration time) × 100%; discrimination index = (new object exploration time-familiar object exploration time)/(new object exploration time + familiar object exploration time) × 100%.
New object recognition is an experimental method widely used to study memory changes. Using this experiment, the effects of candidate drugs on short-term, intermediate-term and long-term memory can be assessed. The results show (fig. 1) that the recognition index of the mice in the sleep deprivation group is significantly reduced, indicating that the time for exploring the new object by the mice is shorter than the time for exploring the familiar object, indicating that the curiosity and the intention of exploring the new object by the mice are reduced, and the cognitive and learning abilities are greatly weakened. The time for the sleep deprived mice to explore the new object is shorter than the time for the mice to explore the familiar object, and the discrimination and memory capacity between the new object and the old object is reduced, which indicates that the sleep deprived mice cannot distinguish the new object from the old object because the memory of the old object is not reserved, and the recognition memory capacity of the new object and the old object is damaged. In contrast, in mice taking CCFM1025, the recognition index and the discrimination index can be kept at the equivalent level of the normal control, and the CCFM1025 is proved to be capable of protecting the normal development of the cognitive memory of the mice.
Example 2: bifidobacterium breve CCFM1025 can improve serotonin turnover rate and melatonin content in brain of sleep deprived mice
Animal models were constructed as in example 1, mice were sacrificed on day 10, mouse brain tissue was removed, and striatum was isolated on ice. The mouse striatum was removed and weighed. The tissue sample was added with 0.4mol/L perchloric acid solution according to 1. Then homogenized with a high throughput tissue disruptor, centrifuged at 12000 Xg at 4 ℃ for 15min, 200-300. Mu.L of the supernatant was aspirated and transferred to a brown sample vial. And detecting the serotonin turnover rate and the melatonin content in the striatum of the mouse by adopting a high performance liquid chromatography. The peak retention time is used for qualitative determination, and the peak area is measured by an external standard method for quantitative determination.
5-HIAA and MT are two metabolites of 5-HT, the former being the major metabolite. The ratio of 5-HIAA to 5-HT (i.e., serotonin turnover rate) reflects the 5-HT content of the free system, as well as the rate of metabolism of 5-HT. As shown in FIG. 2, sleep deprivation resulted in a significant decrease in the level of 5-HT in the striatum and a significant increase in the metabolic rate of 5-HT. It was also observed that melatonin levels in the striatum were significantly reduced in the sleep deprived mice. Melatonin (MT) is known to function primarily to improve sleep quality, shorten wake-up time before sleep and fall-to-sleep, improve sleep quality, significantly reduce the number of awakenings during sleep, shorten the light sleep phase, lengthen the deep sleep phase, and lower the next morning wake-up threshold. Has stronger function of adjusting time difference. Related studies have shown that melatonin secretion is reduced, resulting in difficulty falling asleep and daytime lassitude. The decrease of 5-HT and MT content can affect the normal biological rhythm. Administration of CCFM1025 after sleep deprivation maintained the serotonin turnover rate and melatonin levels in the striatum of mice at levels comparable to those of the normal controls, indicating that it was able to ameliorate circadian rhythm abnormalities.
Example 3: bifidobacterium breve CCFM1025 relieves circadian rhythm related gene expression abnormality caused by sleep deprivation
The animal model was constructed as in example 1, the mice were sacrificed on day 10, and a mass of fresh striatal cortical tissue from the brain tissue of the mice was taken separately and homogenized by adding 1mL of TRIzol and two zirconium beads. Total RNA was extracted by conventional methods. Adjusting the concentration of the reverse transcription system to 1. Mu.g/. Mu.L, purity (A) 260 /A 280 ) The range is 1.8-2.0. And synthesizing cDNA through reverse transcription, and performing real-time quantitative PCR reaction. Samples were mixed with the fluorescent dye SYBR Green super mix in PCR system of 5. Mu.L mix, 1. Mu.L cDNA, 0.5. Mu.L forward and reverse primers, with dd H 2 O is added until the total volume is 10 mu L. In real-time fluorescent quantitative gene amplification instrument CFX384 TM Detection was performed on the Real-Time System (Bio-Rad, USA) with 3 parallel wells per sample, with the housekeeping gene GAPDH as internal reference. The primers used are shown in Table 2. After the reaction is finished, calculating and analyzing each amplification cycle number (Cq); relative expression amounts were expressed as multiples of the target gene for the housekeeping gene (2) -ΔΔCq ) Wherein- Δ Δ Cq = (Cq =) Target gene -Cq Housekeeping gene ) Experimental group -(Cq Target gene -Cq Housekeeping gene ) Control group 。
TABLE 2 primers
| Primer name | Sequence (5 '-3') |
| Per1-F | TGAAGCAAGACCGGGAGAG |
| Per1-R | CACACACGCCATCACATCAA |
| c-Fos-F | CGGGTTTCAACGCCGACTA |
| c-Fos-R | TTGGCACTAGAGACGGACAGA |
| Bdnf-F | TGCAGGGGCATAGACAAAAGG |
| Bdnf-R | CTTATGAATCGCCAGCCAATTCTC |
| GAPDH-F | TCCTGCACCACCAACTGCT |
| GAPDH-R | GTCAGATCCACGACGGACACA |
The per1 rhythm gene plays an important role in the formation and regulation of circadian rhythms as an important component of the circadian system. Relevant research proves that the Per1 mutation and expression deletion mouse has no effect on the regulation of circadian rhythm induced by illumination, shortens the circadian cycle and influences the expression of other clock genes. The formation of c-Fos and memory is associated with the immediate early gene initiation of a cellular cascade leading to neuronal synaptic remodeling. The important immediate early gene c-Fos and its protein product not only directly participate in cell growth, differentiation and intracellular information transmission, but also play a very important role in learning and memory. Bdnf plays an important role in memory formation and long-term enhancement. Research finds that the selective removal of the expression of the mouse brain Bdnf obviously influences the learning ability of the mouse; whereas, injection of recombinant Bdnf into the hippocampus can reverse memory loss due to inhibition of local Bdnf synthesis. As a result, as shown in FIG. 3, the relative expression levels of the genes involved in striatum Per1, c-Fos, bdnf, etc. were decreased by sleep deprivation, indicating that the circadian rhythm of mice was disturbed by sleep deprivation and the memory function was impaired. And CCFM1025 intervention can restore the relative expression quantity of the genes to a level which is close to normal, help mice to restore normal circadian rhythm and improve the cognition and memory ability of the mice.
Example 4: bifidobacterium breve CCFM1025 for improving intestinal flora of sleep deprived mice and synthesis of metabolites thereof
Animal models were constructed as in example 1, taking fresh mouse feces over the end of week 2, and total DNA was extracted from the mouse feces samples using MP feces kit. The specific operation steps are mainly carried out according to the kit instructions. A16S rDNA V3-V4 region fragment was amplified using the mouse fecal genome as a template and the universal primers 341F and 806R. Preparing 2.0% agarose Gel, performing electrophoresis for 40min under the condition of 120V, and after Gel leakage, recovering the target band Gel according to the QIAquick Gel Extraction Kit Gel recovery Kit instructions. The concentration of the Sample DNA is detected according to a Qubit DNA3.0 Kit, then a library is constructed according to the TurSeq DNA LT Sample Preparation Kit and the description thereof, and finally the concentration is determined on an Illumina Miseq sequencer according to the MiSeq Regent Kit and the description thereof. The offboard data were analyzed using QIIME 2.
Calculating alpha-diversity and beta-diversity of the fecal samples to evaluate the flora diversity of the fecal samples. Wherein the beta-diversity is analyzed by Principal coordinate analysis (PCoA)Evaluation was carried out, and it can also be seen from the results that sleep deprivation caused a significant change in the bacterial flora structure in the intestinal tract of mice, while probiotic-administered mice were more similar to the normal group (multiple replacement variance test post hoc multiple comparison result: P) Normal control group vs sleep deprivation group ＝0.003，P Probiotic intervention group vs sleep deprivation group ＝0.002，P Probiotic intervention group vs normal control group >0.05). The α -diversity was characterized by the fragrance index (Shanno index) and the Chao1 index, and the results showed (FIG. 4) that the intestinal flora α -diversity was significantly increased in sleep deprived mice, probably due to the massive proliferation of conditional pathogens in the intestine; while CCFM1025 taken can restore α -diversity to normal. KEGG orthologous gene annotation was performed on the 16S rRNA sequencing results, and the interaction relationship between Gut microbes and the Brain was explored by Gut-Brain Module (GBM) analysis. The module set is helpful for converting intestinal metagenomic data into a potential way for generating neurobiological effect in the brain, particularly relates to metabolites and pathways with the potential of crossing the blood brain barrier, and further better researches the action mechanism of neuropathology and psychopharmaceuticals. The analysis result shows (figure 5), CCFM1025 treatment has significant improvement effect on the synthesis of S-adenosyl-methionine, gamma-aminobutyric acid (GABA) degradation and Isovaleric acid (Isovaleric acid) synthesis pathway of intestinal flora, and the content of the metabolites in the serum is restored to normal level, particularly the content of gamma-aminobutyric acid and Isovaleric acid in the serum is increased, and the content of S-adenosylmethionine precursor, namely adenosine is reduced (figure 6).
Example 5: fermented food containing the bifidobacterium breve CCFM1025 prepared by the invention
Selecting fresh vegetables (such as fructus Cucumidis Sativi, radix Dauci Sativae, beet, herba Apii Graveolentis, caulis et folium Brassicae Capitatae product or their mixture), cleaning, squeezing, sterilizing at 140 deg.C for 2 s, cooling to 37 deg.C, inoculating microbial agent or leaven containing Bifidobacterium breve CCFM1025 to make the concentration of the inoculated Bifidobacterium breve CCFM1025 reach 1 × 10 8 CFU/mL or above, at a temperature of 4 ℃Refrigerating and preserving to obtain the fruit and vegetable beverage containing the live bifidobacterium breve CCFM1025 bacteria.
The bifidobacterium breve CCFM1025 is fermented to produce and prepare other fermented foods, wherein the fermented foods comprise solid foods, liquid foods and semi-solid foods. The fermented food comprises dairy products, bean products and fruit and vegetable products, and the dairy products comprise milk, sour cream and cheese.
The results of the tests carried out in examples 1 to 4, in which the fermented food obtained by the preparation was used as part of the mouse diet, showed that the fermented food was capable of alleviating the abnormality of cognitive and memory functions caused by sleep deprivation, promoting the normal expression of genes related to circadian rhythm, and improving the disturbance of intestinal flora and its metabolites.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Application of Bifidobacterium breve (CCFM 1025) in preparing products for regulating biological circadian rhythm and improving insomnia is provided; the Bifidobacterium breve CCFM1025 is characterized in that the deposit number of the Bifidobacterium breve CCFM1025 is GDMCC No.60386.
2. The use according to claim 1, wherein the product comprises, but is not limited to, a medicament, a functional food, a fermented food, a nutritional supplement or a food additive.
3. The use according to claim 1 or 2, wherein the Bifidobacterium breve CCFM1025 is present in the product in an amount of at least 1 x 10 8 CFU/g or 1X 10 8 CFU/mL。
4. The use according to claim 2 or 3, wherein the product is a fermented food product produced by fermentation using Bifidobacterium breve CCFM1025, the fermented food product comprising a solid food product, a liquid food product, a semi-solid food product.
5. The use of claim 4, wherein the fermented food product comprises a fermented dairy product, a fermented soy product, or a fermented fruit and vegetable product.
6. Use according to claim 5, wherein the dairy product comprises milk, sour cream or cheese; the fruit and vegetable product comprises one or more of cucumber, carrot, beet, celery or cabbage.
7. Use according to any one of claims 1 to 6, characterized in that the regulation of biological circadian rhythms is, in particular, the prevention and/or alleviation of circadian rhythm disturbances caused by insomnia.
8. The use of claim 7, wherein the use further comprises preventing and/or alleviating cognitive and memory impairment caused by insomnia, and increasing the serotonin turnover rate and melatonin content in the brain.
9. The use according to any one of claims 1 to 8, wherein the use further comprises preventing and/or alleviating disturbances of the intestinal flora and the metabolic synthesis thereof caused by insomnia, including at least one of S-adenosylmethionine, γ -aminobutyric acid, isovaleric acid.
10. Application of Bifidobacterium breve (CCFM 1025) in preparing health product for improving sleep; the Bifidobacterium breve CCFM1025 is characterized in that the deposit number of the Bifidobacterium breve CCFM1025 is GDMCC No.60386.
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