WO2025246169A1 - 提高甜味感知能力的格氏乳杆菌bn9、其发酵食品及其应用 - Google Patents

提高甜味感知能力的格氏乳杆菌bn9、其发酵食品及其应用

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WO2025246169A1
WO2025246169A1 PCT/CN2024/128053 CN2024128053W WO2025246169A1 WO 2025246169 A1 WO2025246169 A1 WO 2025246169A1 CN 2024128053 W CN2024128053 W CN 2024128053W WO 2025246169 A1 WO2025246169 A1 WO 2025246169A1
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lactobacillus gasseri
preparation
product
obese
products
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French (fr)
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李莉
赵伟
杨政超
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Jiangnan University
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus

Definitions

  • This invention relates to Lactobacillus gasseri BN9, which enhances the perception of sweetness, its fermented foods, and their applications, and belongs to the field of microbial technology.
  • the gut microbiota often referred to as the "internalized external environment," participates in various physiological activities of the host, including digestion, metabolism, and immunity.
  • the gut-brain axis is a bidirectional communication system between the gut microbiota and the brain; the gut microbiota can influence host brain function and behavior through this axis.
  • gut microbiota can regulate the host's sensory decision-making, influencing responses to odors and food choices; it can also affect the host's perception of sweetness. Therefore, regulating the gut microbiota through probiotics, thereby modulating an individual's sweetness perception and reducing active sugar intake, represents a novel and potential approach.
  • probiotics are mainly to regulate intestinal function; no research has reported that any probiotic can improve individual.
  • the technical problem to be solved by this invention is to provide a probiotic that can effectively improve an individual's ability to perceive sweetness and its application.
  • this invention provides Lactobacillus gasseri BN9, which was deposited on January 28, 2024, at the Guangdong Provincial Microbial Culture Collection Center with accession number GDMCC No:64320. The deposit address is Guangdong Institute of Microbiology, 5th Floor, Building 59, No. 100 Xianlie Middle Road, Guangzhou.
  • the viable count of Lactobacillus gasseri BN9 in the microbial preparation is not less than 1 ⁇ 108 CFU/mL or 1 ⁇ 108 CFU/g.
  • the present invention also provides a product containing the above-mentioned Lactobacillus gasseri BN9 or the above-mentioned microbial preparation.
  • the product includes food, medicine, or health products.
  • the food includes fermented food or feed additive; the fermented food includes dairy products, soy products, fruit and vegetable products or other fermented foods containing Lactobacillus gasseri BN9.
  • the viable count of Lactobacillus gasseri BN9 in the product is not less than 1 ⁇ 108 CFU/mL or 1 ⁇ 108 CFU/g.
  • the fruit and vegetable products include one or more products made from cucumbers, carrots, beets, celery, cabbage, and other edible fruits and vegetables.
  • the fermented food further contains additives, which are selected from one or more combinations of spices, fruit and vegetable juices, flower tea juices, colorants, acidity regulators, preservatives, antioxidants, thickeners, and sweeteners.
  • the fermented food is processed into solid food, liquid food, or semi-solid food.
  • the present invention also provides the use of the above-mentioned Lactobacillus gasseri BN9 or the above-mentioned microbial preparation in the preparation of drugs that enhance the ability to perceive sweetness.
  • the present invention also provides the use of the above-mentioned Lactobacillus gasseri BN9 or the above-mentioned microbial preparation in the preparation of pharmaceuticals or health products that help maintain healthy blood sugar levels.
  • the present invention also provides the application of the above-mentioned Lactobacillus gasseri BN9 or the above-mentioned microbial preparation in the preparation of products that reduce the weight of obese individuals.
  • the Lactobacillus gasseri BN9 provided by this invention has excellent intestinal colonization ability, can significantly improve the sweet taste perception ability of healthy individuals, obese individuals, and diabetic individuals, and has the effect of lowering blood sugar.
  • Lactobacillus gasseri BN9 of the present invention can significantly improve the body's ability to perceive sweetness, significantly increase the content of amino acids such as glutamic acid (7.99 times), glycine (6.02 times), and lysine (6.74 times) in the intestine, and significantly increase the content of amino acids such as glutamine (6.68 times), serine (4.81 times), and glycine (7.02 times) in the blood;
  • Lactobacillus gasseri BN9 of this invention significantly improves the body's sweet taste perception, reduces the weight of obese mice, and improves blood glucose homeostasis.
  • Feeding Lactobacillus gasseri BN9 can increase the preference of obese and diabetic mice for low-concentration sucrose solutions (10 mmol/L and 15 mmol/L sucrose solutions) to normal levels, reduce the weight of obese mice by approximately 21%, reduce peak blood glucose levels by approximately 23.75%, and reduce the area under the oral glucose tolerance test curve by approximately 29.40%; and reduce peak blood glucose levels in diabetic mice by approximately 26.87% and reduce the area under the oral glucose tolerance test curve by approximately 31.58%.
  • the Lactobacillus gasseri BN9 described in this invention can improve an individual's sweet taste perception ability and can be used to prepare related functional foods, health products and pharmaceuticals to reduce an individual's sugar intake. It has a very broad application prospect in regulating taste impairment caused by diseases such as obesity and diabetes and controlling an individual's blood sugar and weight.
  • Lactobacillus gasseri BN9 taxonomically named Lactobacillus gasseri
  • GDMCC No.: 64320 located at the Guangdong Institute of Microbiology, 5th Floor, Building 59, No. 100 Xianlie Middle Road, Guangzhou.
  • Figure 1 shows the effect of Lactobacillus gasseri BN9 on the sweet taste perception ability of individual bumblebees. Lactobacillus gasseri BN9 significantly improved the sweet taste perception ability of individuals; while the control strains Lactobacillus gasseri CN3 and Lactobacillus rhamnosus did not affect the sweet taste perception ability of individuals; **P ⁇ 0.01.
  • Figure 2 shows the effects of feeding Lactobacillus gasseri BN9 on amino acids in the gut and hemolymph of bumblebees.
  • A Differences in hindgut amino acids
  • B Differences in hemolymph amino acids.
  • Figure 3 shows the effect of feeding Lactobacillus gasseri BN9 on sucrose preference in obese mice; *P ⁇ 0.05.
  • Figure 4 shows the effects of feeding Lactobacillus gasseri BN9 on body weight and glucose tolerance in obese mice; (A) body weight; (B) glucose tolerance test; **P ⁇ 0.01.
  • Figure 5 shows the effect of feeding Lactobacillus gasseri BN9 on sucrose preference in diabetic mice; *P ⁇ 0.05.
  • Figure 6 shows the effect of feeding Lactobacillus gasseri BN9 on glucose tolerance in diabetic mice; **P ⁇ 0.01.
  • MRS solid medium tryptone 10.00 g/L, yeast extract 5.00 g/L, beef extract 10.00 g/L, glucose 20.00 g/L, triammonium citrate 2.00 g/L, anhydrous sodium acetate 5.00 g/L, magnesium sulfate 0.10 g/L, manganese sulfate 0.05 g/L, dipotassium hydrogen phosphate 2.00 g/L, Tween 80 1.00 mL/L, agar powder 15.00 g/L, pH adjusted to 6.5.
  • MRS liquid culture medium tryptone 10.00 g/L, yeast extract 5.00 g/L, beef extract 10.00 g/L, glucose 20.00 g/L, triammonium citrate 2.00 g/L, anhydrous sodium acetate 5.00 g/L, magnesium sulfate 0.10 g/L, manganese sulfate 0.05 g/L, dipotassium hydrogen phosphate 2.00 g/L, Tween 80 1.00 mL/L, pH adjusted to 6.5.
  • the ordinary feed involved in this invention was purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., product number XTCON50J; the high-fat feed was purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., product number XTHF60.
  • the blood glucose meter and test strips involved in this invention were purchased from Roche Pharmaceuticals Ltd., model ACCU-CHEK Guide.
  • Lactobacillus gasseri CN3 and Lactobacillus rhamnosus involved in the following examples are self-selected strains.
  • the obtained PCR product was sent to a professional sequencing company for sequencing.
  • the sequencing results were searched and compared for similarity in the GeneBank database using BLAST.
  • the sequencing results identified the strain as belonging to Lactobacillus gasseri and named it Lactobacillus gasseri BN9.
  • the strain was stored at -80°C for later use.
  • Example 2 Effects of Lactobacillus gasseri BN9 on the sweet taste perception ability of individual bumblebees
  • Sweet taste perception tests were conducted on bumblebees at 12 days of age. The specific methods and results are as follows: Individual bumblebees that had been fasted for 12 hours were placed in a tester and given 2 ⁇ l of water (0%) and sucrose solutions of 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, and 40% concentrations, respectively. The feeding behavior of the bumblebees was observed and recorded to assess their sweet taste perception ability. Feeding on sucrose solution indicated that the bumblebees responded to the corresponding concentration of sugar solution.
  • Example 3 Effects of Lactobacillus gasseri BN9 on host amino acid metabolism
  • the content of glutamic acid increased from 0.15 mg/g to 1.26 mg/g, an increase of 7.99 times; the content of lysine increased from 0.14 mg/g to 0.96 mg/g, an increase of 6.74 times; and the content of glycine increased from 0.16 mg/g to 0.98 mg/g, an increase of 6.02 times.
  • feeding with *Lactobacillus gasseri* BN9 significantly increased the levels of amino acids such as glutamine, serine, and glycine in bumblebee hemolymph.
  • Glutamine levels increased from 0.21 mg/g to 1.44 mg/g, a 6.68-fold increase; serine levels increased from 0.28 mg/g to 1.38 mg/g, a 4.81-fold increase; and glycine levels increased from 0.18 mg/g to 1.26 mg/g, a 7.02-fold increase.
  • Glycine and lysine are associated with maintaining brain function and regulating blood sugar; serine is associated with blood sugar regulation and weight control; glutamine and glutamate can be interconverted in the body, and glutamate plays an important role in the transmission and regulation of taste information in taste receptors. Therefore, *Lactobacillus gasseri* BN9 may enhance the sweet taste perception ability of individual bumblebees by regulating the amino acid content in the hindgut and hemolymph.
  • Example 4 Lactobacillus gasseri BN9 can improve the sweet taste perception ability of obese mice.
  • the normal control group was fed a standard diet for 12 weeks; the obese and obese + Lactobacillus gasseri BN9 groups were fed a high-fat diet for 12 weeks.
  • the normal control and obese groups received an equal volume of physiological saline by gavage daily for 4 weeks. The weight of all mice was recorded every two weeks. From week 13, all three groups were fed a standard diet, and subsequent tests were conducted.
  • Example 5 Lactobacillus gasseri BN9 can improve individual obesity symptoms.
  • Example 4 the body weight and oral glucose tolerance test (OGTT) of the three groups of mice were compared. Body weight was recorded every two weeks, and OGTT was measured at week 16 after the glucose preference test. Eight weeks of high-fat diet resulted in significantly higher body weight in the mice compared to the control group. Supplementation with Lactobacillus gasseri BN9 was then initiated at week 9. Compared to the obese group, the obese mice fed with Lactobacillus gasseri BN9 showed an average body weight reduction of 2.03 g and 8.97 g at weeks 10 and 12, respectively. One month of Lactobacillus gasseri BN9 feeding significantly reduced the body weight of obese mice by 21.34% (Figure 4A).
  • mice were fasted for 14 hours but allowed free access to water. Then, each mouse was administered sterile glucose solution by gavage at a dose of 2 g glucose/kg body weight. Blood was collected from the tail of a lancet, and blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 minutes after gavage (0 min represents the fasting blood glucose level before gavage). OGTT curves were plotted, and the area under the curve (AUC) was calculated. Obese mice exhibited impaired glucose tolerance, while supplementation with *Lactobacillus gasseri* BN9 improved glucose tolerance in obese mice.
  • AUC area under the curve
  • Lactobacillus gasseri BN9 can improve the sweet taste perception ability of diabetic mice.
  • the normal control group mice were fed a standard diet for 12 weeks.
  • a high-fat diet was fed for 12 weeks, followed by an 8-week high-fat diet.
  • Mice fed a high-fat diet were then given a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) to induce diabetes and obtain diabetic mice.
  • STZ streptozotocin
  • mice in each group Two identical water bottles were placed in each cage, one containing a sucrose solution with a concentration set to [missing information]. Two solutions were tested: one containing 1, 5, 10, 15, 20, 25, and 50 mmol/L, and the other containing deionized water, ensuring consistent solution volume in both solutions. To avoid errors caused by positional bias, the positions of the two tubes were swapped every 24 hours, and each sugar solution concentration was tested for 48 hours. During testing, the solution concentration was increased sequentially from low to high. Results showed that diabetic mice exhibited a decreased preference for lower concentrations of sucrose solution, while feeding Lactobacillus gasseri BN9 significantly improved their preference for lower concentrations, restoring it to a level comparable to the control group.
  • the preference rate was 57.96% in diabetic mice fed with Lactobacillus gasseri BN9, compared to 60.32% in the control group and 52.9% in diabetic mice; for a 15 mmol/L sucrose solution, the preference rate was 60.21% in mice fed with Lactobacillus gasseri BN9, compared to 62.53% in the control group and 54.86% in diabetic mice. It is evident that diabetic mice have a decreased ability to perceive sweetness, while Lactobacillus gasseri BN9 can improve the ability to perceive sweetness in diabetic mice (Figure 5).
  • Activated Lactobacillus gasseri BN9 was cultured anaerobically at 37°C for 48 hours in MRS liquid medium. 30 mL of the Lactobacillus gasseri BN9 culture was placed in a centrifuge tube and centrifuged at 4°C and 4000 rpm for 10 min. The supernatant was discarded, and the bacterial sludge was collected. After washing 2-3 times with strictly sterilized physiological saline, an appropriate amount of cryoprotectant was added and mixed thoroughly. The mixture was pre-cooled at -80°C for 4 hours and then freeze-dried under the following conditions: cold trap temperature -70°C, drying time 24 hours, and vacuum degree 1 Pa. After freeze-drying, the bacterial powder was immediately collected into aseptic packaging bags and sealed to obtain Lactobacillus gasseri BN9 bacterial agent.
  • Fresh milk and white sugar were mixed and homogenized (5:1), sterilized at 140°C for 2 seconds, cooled to 35°C, and then inoculated with the Lactobacillus gasseri BN9 inoculum prepared in this invention.
  • the mixture was sealed and fermented at 35°C for 4 hours, and then transferred to a refrigerator at 4°C for 12 hours for post-ripening to obtain the final fermented product (bacterial concentration above 108 CFU/mL).
  • This invention enables the production and preparation of other fermented foods using Lactobacillus gasseri BN9 fermentation.
  • These fermented foods include solid foods, liquid foods, and semi-solid foods.
  • the fermented foods include dairy products, soy products, and fruit and vegetable products.
  • Products include milk, sour cream, and cheese; the fruit and vegetable products include cucumber, carrot, beet, celery, and cabbage products.

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Abstract

公开了提高甜味感知能力的格氏乳杆菌BN9、其发酵食品及其应用，涉及微生物技术领域。服用所述格氏乳杆菌BN9能够显著提高健康机体的甜味感知能力，调节肠道氨基酸的代谢；同时，服用所述格氏乳杆菌BN9能够显著提高肥胖机体和糖尿病机体的甜味感知能力，并降低肥胖小鼠的体重，改善肥胖和糖尿病个体的血糖稳态。综上所述，所述格氏乳杆菌BN9能够用于制备改善、提高个体甜味感知能力的功能食品、保健品和药品，在调节由于肥胖和糖尿病等疾病引起的味觉损伤和控制个体血糖等方面具有非常广阔的应用前景。

Description

提高甜味感知能力的格氏乳杆菌BN9、其发酵食品及其应用 技术领域
本发明涉及提高甜味感知能力的格氏乳杆菌BN9、其发酵食品及其应用，属于微生物技术领域。
背景技术
人类对糖的喜爱是与生俱来的，目前我国糖的消费量巨大并在逐年增加。近年来，糖的摄入与不良健康效应的关系备受关注，控制糖的摄入成为人们日益关注的话题。糖分摄入过多是导致以糖脂代谢稳态失衡为主要特征的代谢性疾病，如二型糖尿病、肥胖、心血管疾病的重要危险因素。针对青少年、成年人和老年人等不同人群的控制糖分摄入的方法主要包括减少糖的添加、控制饮食、使用甜味剂和服用特定药物抑制食欲等。然而，这些控糖方法存在一定的不足，例如，减少糖的添加会导致食品口感变差、控制饮食较难长期坚持并会导致营养摄入不均衡、甜味剂和药物的成本高昂且存在潜在的副作用。此外，这些控糖方法使人们无法享受美食带来的愉悦，可能引发不同的心理健康问题。从增强个体甜味感知的角度进行控糖可以避免这些缺点，具有明显的优势，无需改变饮食结构，通过减少糖的添加就可实现控糖的效果，且饮食者具有良好的口感体验，最终减少肥胖、糖尿病等疾病的发生。另外，肥胖症、糖尿病等疾病可能导致患者味觉退化或损伤，使其食而无味或更嗜甜，但目前尚无有效提高个体甜味感知能力的安全药物。因此，增强机体甜味感知不仅可以有效控制糖分的摄入量，减少糖尿病、肥胖等疾病的发生，还对辅助治疗味觉退化或损伤具有重要意义。
肠道菌群被称为“内化的外环境”，参与宿主的消化、代谢、免疫等多种生理活动。肠-脑轴是肠道菌群与大脑之间的双向信息交流系统，肠道菌群可通过肠-脑轴影响宿主大脑功能与行为。例如，研究发现肠道菌可以调控宿主的感官决策，影响其对气味等的反应及对食物的选择；肠道菌群可以影响宿主对甜味的感知。因此，通过益生菌调节肠道菌群进而调节个体的甜味感知能力以减少糖的主动摄入是一种新的可能方法。
目前已知益生菌的功能主要为调节肠道功能、提高宿主营养代谢等，而已知的可提高甜味感知能力的益生菌种类非常少。因此，筛选可提升个体甜味感知能力的益生菌，并开发出辅助减糖、控糖或治疗味觉退化的产品具有极为广阔的应用前景。
发明内容
[技术问题]
目前已知的益生菌的功能主要为调节肠道功能，没有任何研究报道某种益生菌可提高个 体的甜味感知能力，本发明要解决的技术问题是提供一种能有效提高个体甜味感知能力的益生菌及其应用。
[技术方案]
为解决本发明的技术问题，本发明提供了一种格氏乳杆菌(Lactobacillus gasseri)BN9，于2024年1月28日保藏于广东省微生物菌种保藏中心，保藏编号为GDMCC No:64320，保藏地址为广州市先烈中路100号大院59号楼5楼广东省微生物研究所。
本发明还提供了含有上述格氏乳杆菌BN9的微生物制剂。
在本发明的一种实施方式中，所述微生物制剂中，上述格氏乳杆菌BN9的活菌数不低于1×108CFU/mL或1×108CFU/g。
本发明还提供了一种产品，所述产品含有上述格氏乳杆菌BN9或上述微生物制剂。
在本发明的一种实施方式中，所述产品包括食品、药品或保健品。
在本发明的一种实施方式中，所述食品包括发酵食品或饲料添加剂；所述发酵食品包括乳制品、豆制品、果蔬制品或其他含有格氏乳杆菌BN9的发酵食品。
在本发明的一种实施方式中，所述产品中，上述格氏乳杆菌BN9的活菌数不低于1×108CFU/mL或1×108CFU/g。
在本发明的一种实施方式中，所述乳制品包括牛奶、酸奶油、干酪。
在本发明的一种实施方式中，所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜以及其他可食用的果蔬中的一种或两种以上的制品。
在本发明的一种实施方式中，所述发酵食品还含有添加剂，所述添加剂选自香料、果蔬汁、花茶汁、着色剂、酸度调节剂、防腐剂、抗氧化剂、增稠剂、甜味剂中的一种或两种以上的组合。
在本发明的一种实施方式中，所述发酵食品的加工形态包括固态食品、液态食品或半固态食品。
本发明还提供了上述格氏乳杆菌BN9或上述微生物制剂在制备提高甜味感知能力的药物中的应用。
本发明还提供了上述格氏乳杆菌BN9或上述微生物制剂在制备有助于维持血糖健康水平的药品或保健品中的应用。
本发明还提供了上述格氏乳杆菌BN9或上述微生物制剂在制备降低肥胖机体体重的产品中的应用。
有益效果：
本发明提供的格氏乳杆菌BN9具有良好的肠道定植能力，能够显著提高健康个体、肥胖个体和糖尿病个体的甜味感知能力，并具有降低血糖的功效：
1、对于健康个体，服用本发明的格氏乳杆菌BN9能够显著提高机体的甜味感知能力，显著提高了肠道中谷氨酸(7.99倍)、甘氨酸(6.02倍)和赖氨酸(6.74倍)等氨基酸的含量，并显著提高了血液中谷氨酰胺(6.68倍)、丝氨酸(4.81倍)和甘氨酸(7.02倍)等氨基酸的含量；
2、对于肥胖个体和糖尿病个体，服用本发明的格氏乳杆菌BN9能够显著提高机体的甜味感知能力，降低肥胖小鼠的体重，改善机体血糖稳态。饲喂格氏乳杆菌BN9可使肥胖小鼠和和糖尿病小鼠对低浓度蔗糖溶液(10mmol/L和15mmol/L蔗糖溶液)的偏好提升到正常水平，使肥胖小鼠的体重降低约21％，血糖峰值降低约23.75％，口服葡萄糖耐量试验曲线下面积减少约29.40％；使糖尿病小鼠血糖峰值降低约26.87％，口服葡萄糖耐量试验曲线下面积减少约31.58％。
综上所述，本发明所述的格氏乳杆菌BN9能够提高个体的甜味感知能力，可用于制备相关的功能食品、保健品和药品以减少个体的糖摄入，在调节由于肥胖和糖尿病等疾病引起的味觉损伤和控制个体血糖、体重等方面具有非常广阔的应用前景。
生物材料保藏
一种格氏乳杆菌(Lactobacillus gasseri)BN9，分类学命名为Lactobacillus gasseri，已于2024年1月28日保藏于广东省微生物菌种保藏中心，保藏编号为GDMCC No：64320，保藏地址为广州市先烈中路100号大院59号楼5楼广东省微生物研究所。
附图说明
图1为格氏乳杆菌BN9对熊蜂个体甜味感知能力的影响。格氏乳杆菌BN9可显著提高个体甜味感知能力；而对照菌株格氏乳杆菌CN3和Lactobacillus rhamnosus不影响个体的甜味感知能力；**P<0.01。
图2为饲喂格氏乳杆菌BN9对熊蜂肠道和血淋巴中氨基酸的影响。(A)后肠氨基酸的不同；(B)血淋巴氨基酸的不同。
图3为饲喂格氏乳杆菌BN9后对肥胖小鼠蔗糖偏好的影响；*P<0.05。
图4为饲喂格氏乳杆菌BN9后对肥胖小鼠体重及葡萄糖耐量的影响；(A)体重；(B)葡萄糖耐量检测；**P<0.01。
图5为饲喂格氏乳杆菌BN9对糖尿病小鼠蔗糖偏好的影响；*P<0.05。
图6为饲喂格氏乳杆菌BN9对糖尿病小鼠葡萄糖耐量的影响；**P<0.01。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解实施例是为了更好地解释本发明，不用于限制本发明。
下述实施例中涉及的培养基如下：
MRS固体培养基：胰蛋白胨10.00g/L，酵母提取物5.00g/L，牛肉浸膏10.00g/L，葡萄糖20.00g/L，柠檬酸三铵2.00g/L，无水乙酸钠5.00g/L，硫酸镁0.10g/L，硫酸锰0.05g/L，磷酸氢二钾2.00g/L，吐温80 1.00mL/L，琼脂粉15.00g/L，培养基pH调至6.5。
MRS液体培养基：胰蛋白胨10.00g/L，酵母提取物5.00g/L，牛肉浸膏10.00g/L，葡萄糖20.00g/L，柠檬酸三铵2.00g/L，无水乙酸钠5.00g/L，硫酸镁0.10g/L，硫酸锰0.05g/L，磷酸氢二钾2.00g/L，吐温80 1.00mL/L，培养基pH调至6.5。
本发明涉及的普通饲料购自江苏省协同医药生物工程有限责任公司，货号为XTCON50J；高脂饲料购自江苏省协同医药生物工程有限责任公司，货号为XTHF60。本发明涉及的血糖仪和试纸购自罗氏制药有限公司，型号为ACCU-CHEK Guide。
下述实施例中涉及的格氏乳杆菌CN3和鼠李糖乳酪杆菌为自行筛选菌株。
下述实施例中涉及的其他实验材料均可通过常规渠道购买获得。
实施例1菌株筛选与鉴定
(一)格氏乳杆菌的分离筛选：
(l)取健康女性哺乳期的母乳，梯度稀释后涂布于MRS固体培养基，置于厌氧环境下37℃培养72小时；
(2)观察记录菌落形态，挑取菌落划线纯化；
(3)挑取单菌落，在MRS液体培养基中，37℃培养48小时后收集菌体用于菌株鉴定。
(二)格氏乳杆菌的分子生物学鉴定：
(l)使用E.Z.N.A.Stool DNA试剂盒(Omega Bio-tek)提取单菌基因组DNA；
(2)使用细菌菌种鉴定通用引物扩增16S rDNA；
(3)制备1％琼脂糖凝胶，将PCR产物与loading buffer混合后上样，150V、100mA跑20min，观察并切胶；
(4)将得到的PCR产物送专业测序公司进行测序，使用BLAST将得到的测序结果在GeneBank数据库中进行搜索和相似性比对，测序结果鉴定为该菌株属于格氏乳杆菌，并命名为格氏乳杆菌BN9。菌株-80℃保藏备用。
实施例2格氏乳杆菌BN9对熊蜂个体甜味感知能力的影响
活化的格氏乳杆菌BN9在MRS液体培养基中，37℃厌氧培养，培养48小时；将对照菌株格氏乳杆菌CN3和L.rhamnosus(鼠李糖乳酪杆菌)活化并接种于MRS液体培养基中，37℃厌氧培养，培养48小时。将新鲜的稳定期细菌培养液离心，PBS清洗后，将菌沉淀溶解在40％(w/w)的蔗糖水中，使菌浓度达到OD600＝1.0。
每日对新出房的工蜂进行标记，3日龄时将其转移至不同的小木箱进行分组饲喂，共4组，每组15只蜂，具体分组情况如下：(1)对照组：每日提供40％(w/w)的蔗糖水；(2)格氏乳杆菌BN9饲喂组：提供每日新配的含有格氏乳杆菌BN9(OD600＝1)的40％蔗糖水；(3)格氏乳杆菌CN3饲喂组：提供每日新配的含有格氏乳杆菌CN3(OD600＝1)的40％蔗糖水(4)对照菌株L.rhamnosus饲喂组(L.Rh饲喂组)：提供每日新配的含有L.rhamnosus(OD600＝1)的40％蔗糖水。每日为每组熊蜂提供足量的相应糖水供其自由饮用，共饲喂9天。
熊蜂12日龄时对其进行甜味感知测试，具体实施方法和结果如下：将禁食12h的熊蜂个体放入测试器内，依次给予2μl水(0％)和0.1％、0.25％、0.5％、0.75％、1％、1.25％、1.5％、2％、3％、4％、5％、10％、20％、30％、40％的蔗糖溶液进行测试，观察并记录熊蜂的进食情况以评估其甜味感知能力，进食蔗糖溶液代表熊峰对相应浓度的糖水有反应。每次测试间隔，用浓度为70％的酒精清理擦拭测试器，确保无气味或糖水残留而影响结果。结果如图1所示，与对照组相比，饲喂格氏乳杆菌BN9能够显著提高个体的甜味感知能力，个体对糖水反应的浓度降低，对照组中约有66.7％的个体对1.25％及以上浓度的糖水反应，仅33.3％的个体对1％及以下浓度的糖水反应，而饲喂格氏乳杆菌BN9组中全部个体对1％及以下浓度的糖水反应，即更多的个体对低浓度糖水反应。而对照菌格氏乳杆菌CN3和鼠李糖乳酪杆菌不影响个体的甜味感知能力。
行为实验结束后，采集熊蜂的后肠用于肠道菌群的定量分析，结果显示，格氏乳杆菌BN9可以在熊蜂肠道中定植，其丰度约为106，且不影响肠道的总菌量和其他核心菌的量。
实施例3格氏乳杆菌BN9对宿主氨基酸代谢的影响
将对照组(每日提供40％的蔗糖水)和格氏乳杆菌BN9饲喂组的熊蜂置于干冰上窒息，随后解剖提取出熊蜂的后肠组织和血淋巴。分别将组织样品用分析天平进行称量并详细记录重量，加入500μl 5％三氯乙酸(m/v)，将样品于全自动样品研磨仪中进行组织破碎，混匀样品后常温超声20min，并至少静置2h以沉淀蛋白质。将样品于15000rpm、25℃下离心30min，取上清液用0.22μm水膜过滤后进行HPLC上机检测。
结果显示，饲喂格氏乳杆菌BN9可分别改变熊蜂后肠和血淋巴中的甘氨酸、赖氨酸、丝 氨酸、谷氨酰胺和谷氨酸等多种氨基酸的含量(图2)。饲喂格氏乳杆菌BN9显著提高了熊蜂肠道中谷氨酸、甘氨酸和赖氨酸等氨基酸的含量，谷氨酸含量从0.15mg/g提高至1.26mg/g，提高了7.99倍；赖氨酸含量从0.14mg/g提高至0.96mg/g，提高了6.74倍；甘氨酸含量从0.16mg/g提高至0.98mg/g，提高了6.02倍。同时，饲喂格氏乳杆菌BN9显著提高了熊蜂血淋巴中谷氨酰胺、丝氨酸和甘氨酸等氨基酸的含量，谷氨酰胺含量从0.21mg/g提高至1.44mg/g，提高了6.68倍；丝氨酸含量从0.28mg/g提高至1.38mg/g，提高了4.81倍；甘氨酸含量从0.18mg/g提高至1.26mg/g，提高了7.02倍。甘氨酸和赖氨酸与维持大脑功能和调节血糖等功能相关；丝氨酸与血糖调节和体重调控相关；谷氨酰胺与谷氨酸在体内可进行互相转换，谷氨酸在味蕾感受器的味觉信息传递和调控过程中发挥着重要的作用。因此，格氏乳杆菌BN9可能通过调控熊蜂后肠和血淋巴中氨基酸含量提升个体的甜味感知能力。
实施例4格氏乳杆菌BN9可改善肥胖小鼠的甜味感知能力
本实施例选用C57BL/6J雄性小鼠30只，将上述小鼠随机分为三组(n＝10)，包括正常组、肥胖组和肥胖+格氏乳杆菌BN9组。对于正常组小鼠，用普通饲料饲喂12周；对于肥胖组和肥胖+格氏乳杆菌BN9组小鼠，用高脂饲料饲喂12周，从第9周开始对肥胖+格氏乳杆菌BN9组的小鼠进行格氏乳杆菌BN9的干预，每日灌胃含有格氏乳杆菌BN9(OD600＝1)的PBS溶液200μL，同时每天对正常组和肥胖组的小鼠进行等体积生理盐水的灌胃，灌胃持续4周。所有小鼠每两周记录一次体重。第13周开始对三组小鼠进行普通饲料饲喂，并进行后续测试。
对各组小鼠进行糖水偏好实验，每笼放置两个相同的饮水瓶，一瓶为蔗糖溶液，浓度设置分别为1、5、10、15、20、25、50、100mmol/L，另一瓶为去离子水，使两瓶内溶液量保持一致，为避免位置偏好引起的误差，每24小时将双管位置交换一次，每个糖溶液浓度测试48小时。测试时，溶液浓度依次从低到高进行，记录实验数据。依据公式：蔗糖偏好率(％)＝(蔗糖溶液饮用量/(蔗糖溶液饮用量+去离子水饮用量))×100％，计算小鼠对不同浓度蔗糖溶液的偏好率。
结果显示，与正常小鼠相比，肥胖小鼠对较低浓度蔗糖溶液(10mmol/L和15mmol/L蔗糖溶液)的偏好率降低，而饲喂格氏乳杆菌BN9可显著提高其对较低浓度蔗糖溶液的偏好率。对于10mmol/L蔗糖溶液，饲喂格氏乳杆菌BN9的肥胖小鼠偏好率为58.13％，对照组小鼠为59.21％，而肥胖小鼠偏好率为53.52％；对于15mmol/L蔗糖溶液，饲喂格氏乳杆菌BN9的小鼠偏好率为63.21％，对照组小鼠为65.45％，而肥胖小鼠偏好率为55.12％。饲喂格氏乳杆菌BN9使肥胖小鼠对较低浓度蔗糖溶液的偏好率恢复至与对照组相当的水平。可见肥胖小鼠的 甜味感知能力下降，而格氏乳杆菌BN9可改善肥胖小鼠的甜味感知能力(图3)。
实施例5格氏乳杆菌BN9可改善个体肥胖症状
对实施例4中三组小鼠进行体重和口服葡萄糖耐量(Oral glucose tolerance test，OGTT)的比较，体重每两周记录一次，在糖水偏好测试结束后，在第16周进行口服葡萄糖耐量的测定。8周的高脂饮食使小鼠的体重显著高于普通饲料饲喂组的小鼠，随后在第9周开始补充格氏乳杆菌BN9，与肥胖组小鼠相比，饲喂格氏乳杆菌BN9的肥胖小鼠在第10周和第12周的平均体重分别下降了2.03g和8.97g，饲喂格氏乳杆菌BN9一个月后会显著降低肥胖小鼠的体重，可降低21.34％(图4A)。
进一步进行葡萄糖耐量检测以评估格氏乳杆菌BN9对血糖稳态的影响。控制小鼠禁食不禁水14h，之后按照每只小鼠2g葡萄糖/kg体重的剂量灌胃无菌葡萄糖溶液，以采血针尾部取血，使用血糖仪和试纸测定小鼠灌胃葡萄糖后0、15、30、60、90、120min时的血糖值(0min即为小鼠灌胃前的空腹血糖值)，绘制OGTT曲线并计算曲线下面积(Area under curve，AUC)。肥胖组小鼠出现葡萄糖耐量减退，而补充了格氏乳杆菌BN9则改善了肥胖小鼠的葡萄糖耐量。三组小鼠的血糖峰值均出现在第15min，随后逐渐降低，2h后恢复正常水平。与对照组相比，肥胖小鼠15min血糖峰值和OGTT曲线下面积显著升高，可见肥胖小鼠的葡萄糖耐量减退。饲喂格氏乳杆菌BN9的肥胖小鼠的葡萄糖耐受性得到改善，血糖峰值比肥胖组小鼠下降了约23.75％，OGTT曲线下面积减少了约29.4％(图4B)。以上结果表明格氏乳杆菌BN9具有良好的降低体重、提高血糖稳态的效果。
实施例6格氏乳杆菌BN9可改善糖尿病小鼠的甜味感知能力
本实施例选用C57BL/6雄性小鼠30只，将上述小鼠随机分为对照组(10只)、糖尿病对照组(10只)和糖尿病格氏乳杆菌BN9干预组(10只)。正常组小鼠用普通饲料饲喂12周。对于糖尿病对照组和糖尿病格氏乳杆菌BN9干预组小鼠，饲喂高脂饲料12周，高脂饮食8周后，对用高脂饲料饲喂的小鼠进行单次腹腔注射链脲佐菌素(Streptozotocin，STZ，50mg/kg)，诱发糖尿病以获得糖尿病小鼠。其中10只糖尿病小鼠给予格氏乳杆菌BN9干预，从第9周开始对糖尿病格氏乳杆菌BN9干预组的小鼠进行格氏乳杆菌BN9的干预，每日灌胃含有格氏乳杆菌BN9(OD600＝1)的PBS溶液200μL(糖尿病格氏乳杆菌BN9干预组)；另外10只糖尿病小鼠不给予格氏乳杆菌干预(糖尿病对照组)；每日对对照组和糖尿病对照组的小鼠进行等体积生理盐水的灌胃，灌胃持续4周(9-12周)。第13周开始对三组小鼠进行普通饲料饲喂，并进行后续测试。
对各组小鼠进行糖水偏好实验，每笼放置两个相同的饮水瓶，一瓶为蔗糖溶液，浓度设 置分别为1、5、10、15、20、25、50mmol/L，另一瓶为去离子水，使两瓶内溶液量保持一致，为避免位置偏好引起的误差，每24小时将双管位置交换一次，每个糖溶液浓度测试48小时。测试时，溶液浓度依次从低到高进行。结果显示，糖尿病小鼠对较低浓度蔗糖溶液的偏好率降低，而饲喂格氏乳杆菌BN9可显著提高其对较低浓度蔗糖溶液的偏好率，使其恢复至与对照组相当的水平，其中对于10mmol/L蔗糖溶液，饲喂格氏乳杆菌BN9的糖尿病小鼠偏好率为57.96％，对照组小鼠为60.32％，而糖尿病小鼠为52.9％；对于15mmol/L蔗糖溶液，饲喂格氏乳杆菌BN9的小鼠偏好率为60.21％，对照组小鼠为62.53％，而糖尿病小鼠为54.86％。可见糖尿病小鼠的甜味感知能力下降，而格氏乳杆菌BN9可提高糖尿病小鼠的甜味感知能力(图5)。
糖水偏好测试结束后，参照实施例5的方法，在第16周进行口服葡萄糖耐量比较实验，通过进行葡萄糖耐量检测以评估格氏乳杆菌BN9对糖尿病小鼠血糖稳态的影响。糖尿病小鼠出现葡萄糖耐量减退，而补充了格氏乳杆菌BN9则改善了糖尿病小鼠的葡萄糖耐量。三组小鼠的血糖峰值均出现在第15min，随后逐渐降低，2h后恢复正常水平。与对照组相比，糖尿病小鼠15min血糖峰值和OGTT曲线下面积显著升高，可见糖尿病小鼠出现葡萄糖耐量减退。饲喂格氏乳杆菌BN9的糖尿病小鼠的葡萄糖耐受性得到改善，血糖峰值比糖尿病组小鼠下降了约26.87％，OGTT曲线下面积减少了约31.58％(图6)。以上结果表明，格氏乳杆菌BN9具有良好的提高血糖稳态的效果。
实施例7格氏乳杆菌BN9的应用
格氏乳杆菌BN9菌剂的制备：
活化的格氏乳杆菌BN9在MRS液体培养基中，37℃厌氧培养，培养48小时；取30mL格氏乳杆菌BN9菌液置于离心管中，于4℃、4000rpm的条件下离心10min，弃去上清液，收集菌泥，经严格灭菌的生理盐水洗涤2-3次后，加入适量保护剂混匀，于-80℃预冷4小时后进行冷冻干燥，条件为：冷阱温度-70℃，干燥时间24小时，真空度1Pa。冷冻干燥结束后，立即收集菌粉于无菌包装袋中并塑封，得到格氏乳杆菌BN9菌剂。
格氏乳杆菌BN9发酵牛乳的制备：
将鲜牛乳和白砂糖混匀后均质(5:1)，于140℃杀菌2秒后冷却至35℃，再接入本发明制备的格氏乳杆菌BN9菌剂发酵剂，35℃密封发酵4小时，然后转移至4℃冰箱中放置12小时进行后熟，得到最终发酵产品(菌浓度108CFU/mL以上)。
利用本发明能够使用格氏乳杆菌BN9发酵生产制备其他发酵食品，所述发酵食品包括固态食品、液态食品和半固态食品。所述发酵食品包括乳制品、豆制品和果蔬制品，所述乳制 品包括牛奶、酸奶油和干酪；所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜和圆白菜制品。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。

Claims (10)

  1. 一种格氏乳杆菌(Lactobacillus gasseri)BN9，于2024年1月28日保藏于广东省微生物菌种保藏中心，保藏编号为GDMCC No：64320，保藏地址为广州市先烈中路100号大院59号楼5楼广东省微生物研究所。
  2. 含有权利要求1所述的格氏乳杆菌BN9的微生物制剂。
  3. 如权利要求2所述的微生物制剂，其特征在于，所述微生物制剂中，权利要求1所述的格氏乳杆菌BN9的活菌数不低于1×108CFU/mL或1×108CFU/g。
  4. 一种产品，其特征在于，所述产品含有权利要求1所述的格氏乳杆菌BN9，或权利要求2或3所述的微生物制剂。
  5. 如权利要求4所述的产品，其特征在于，所述产品包括食品、药品或保健品。
  6. 如权利要求5所述的产品，其特征在于，所述食品包括发酵食品或饲料添加剂；所述发酵食品包括乳制品、豆制品、果蔬制品。
  7. 如权利要求4～6任一所述产品，其特征在于，所述产品中，权利要求1所述格氏乳杆菌BN9的活菌数不低于1×108CFU/mL或1×108CFU/g。
  8. 权利要求1所述的格氏乳杆菌BN9，或权利要求2或3所述的微生物制剂在制备缓解和/或治疗味觉退化的药品中的应用。
  9. 权利要求1所述的格氏乳杆菌BN9，或权利要求2或3所述的微生物制剂在制备有助于维持血糖健康水平的药品或保健品中的应用。
  10. 权利要求1所述的格氏乳杆菌BN9，或权利要求2或3所述的微生物制剂在制备降低肥胖机体体重的产品中的应用。
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