Compositions for improving immunity

Abstract

This application provides a probiotic composition comprising *Bifidobacterium bifidum* and *Bifidobacterium longum*. This application also provides a prebiotic composition comprising xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. This application further provides dietary compositions comprising the above-mentioned probiotic and prebiotic compositions. This application further provides uses of the above-mentioned compositions.

Description

[Technical Field]

[0001] This application generally relates to the fields of pharmaceuticals, food, and health products. Specifically, this application provides compositions and their uses that enhance individual immunity or assist in the treatment and prevention of diseases or improve the efficacy of disease treatment based on the regulation of gut microbiota. Related Applications This application claims priority to Chinese Patent Applications 202010657312.5 and 202011259564.9, the entire contents of which are incorporated herein by reference. This application also claims priority to U.S. Provisional Application No. 63 / 016,759, filed April 28, 2020; U.S. Provisional Application No. 63 / 025,310, filed May 15, 2020; and U.S. Provisional Application No. 63 / 064,821, filed August 12, 2020, the entire contents of which are incorporated herein by reference. [Previous Technology]

[0002] The gut microbiota of humans and animals contains a diverse range of bacteria with complex compositions, and there are numerous research reports on the gut microbiota. The gut microbiota is not only related to digestive function, but also to the body's ability to resist pathogen infection, autoimmune diseases, and even the response to drug treatment. Among the gut microbiota are a class of beneficial bacteria called probiotics. Generally, probiotics are active microorganisms that colonize the human body and alter the composition of the gut microbiota in a specific part of the host, thus producing beneficial health effects. Probiotics can promote nutrient absorption and maintain gut health by regulating the host's mucosal and systemic immune functions or by regulating the balance of gut microbiota, thereby producing health-promoting effects. Common probiotics include Bifidobacteria, Lactobacillus, and yeast. Some substances are closely related to probiotics and are called prebiotics. Generally, prebiotics refer to organic substances that are not digested and absorbed by the host but can selectively promote the metabolism and proliferation of probiotics in the body, thereby improving the host's health. Under normal circumstances, most prebiotics should not be digested during passage through the upper digestive tract but should be fermented by the gut microbiota. Most importantly, prebiotics stimulate the growth of beneficial bacteria without stimulating potentially pathogenic or putrefactive bacteria. Common prebiotics include oligosaccharides, also known as dietary fiber. Regulating the gut microbiota through probiotics / prebiotics to promote overall health (e.g., boosting immunity) has been a long-standing research topic in this field. [Summary of the Invention]

[0003] In a first embodiment, this application provides a probiotic composition comprising *Bifidobacterium bifidum* and *Bifidobacterium longum*. In some embodiments, the ratio of *Bifidobacterium bifidum* to *Bifidobacterium longum*, in colony-forming units, is 1:(0.21-2.36). In some embodiments, the probiotic composition further comprises *Bifidobacterium adolescentis*. In some embodiments, the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*, in colony-forming units, is (0.57-3.56):1:(0.21-2.36). In some specific embodiments, the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*, in colony-forming units, is (0.75-1):1:(0.75-1). In some embodiments, the probiotic composition also includes *Lactobacillus rhamnosus*. In some embodiments, the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*, in colony-forming units, is (0.57–3.36):1:(0.21–2.36):1. In some embodiments, the probiotic composition is in unit dose form, and the amounts of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*, in colony-forming units, are independently in the order of 10⁴ to 10¹² CFU. In some embodiments, the total amount of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus* is in the order of 10⁶ to 10¹² CFU. In some embodiments, the probiotic composition is administered to adults, and the amount of *Bifidobacterium adolescentis* is 2.59 × 10⁵ - 4.49 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.26 × 10⁵ - 7.35 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 2.23 × 10⁵ - 7.02 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.26 × 10⁵ - 2.59 × 10¹¹ CFU. In some embodiments, the probiotic composition is intended for administration to children, and the amount of *Bifidobacterium adolescentis* is 2.05 × 10⁵ – 4.55 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.47 × 10⁵ – 3.6 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 7.55 × 10⁴ – 2.5 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.47 × 10⁵ – 3.6 × 10¹¹ CFU. In some embodiments, the probiotic composition does not contain any probiotics other than those specified in the various embodiments of this application.In some embodiments, the probiotic composition does not contain any probiotics other than *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*. In some embodiments, the probiotic composition does not contain any Bifidobacterium other than *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*. In a second embodiment, this application provides a prebiotic composition comprising xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. In some embodiments, the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, by weight, is (0.25-5):(0.75-4):(0.5-1). In some specific embodiments, the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, by weight, is (0.25-0.5):(2-4):(0.5-0.75). In some embodiments, the prebiotic component is in unit dose form, and the total amount of xylooligosaccharides, galactooligosaccharides, and corn fiber is 0.1-12 g by weight. In some embodiments, the prebiotic component is in unit dose form, and the total amount of xylooligosaccharides, galactooligosaccharides, and corn fiber is 0.1-5 g by weight. In some embodiments, the amount of xylooligosaccharides is 0.01 g-6 g; and / or the amount of galactooligosaccharides is 0.04 g-9.6 g; and / or the amount of corn dietary fiber is 0.01 g-6 g. In some embodiments, the prebiotic component does not contain prebiotic components other than xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. In a third aspect, this application provides a dietary component (sometimes also referred to as a "synbiotics" component) comprising the probiotic component of the first embodiment and the prebiotic component of the second embodiment. In some specific embodiments, the dietary composition comprises *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum* as probiotics, and xylooligosaccharides, galactooligosaccharides, and corn dietary fiber as prebiotics. The ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*, based on colony-forming units (CFU), is (0.75-1):1:(0.75-1), and the total amount of the three bacteria is approximately 2 × 10¹¹ CFU. The ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, based on weight, is (0.25-0.5):(2-4):(0.5-0.75), and the total amount of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber is 1.2-1.5 g. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is formulated for oral administration. In some embodiments, oral administration includes oral administration, mixing with oral products, tube feeding, etc. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is a food supplement, food additive, or food.In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is formulated as a powder, granules, tablet, or capsule. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is administered to an individual to assist in the prevention and / or treatment of pathogen infection, or to enhance the therapeutic effect of pathogen infection, or to improve the individual's immunity, or to balance the individual's gut microbiota (including increasing microbial abundance, increasing desirable bacterial species, and / or reducing undesirable bacteria). In some embodiments, the pathogen is a virus, bacteria, or fungus. In some embodiments, the pathogen is a respiratory disease virus, such as SARS-CoV-2, influenza, or respiratory syncytial virus. The fourth embodiment provides the use of a probiotic composition of the first embodiment, a prebiotic composition of the second embodiment, or a dietary composition of the third aspect in the preparation of a dietary product or medicine for assisting in the prevention and / or treatment of pathogen infection in an individual, or enhancing the therapeutic effect of pathogen infection in an individual, or improving the individual's immunity, or balancing the individual's gut microbiota (including increasing microbial abundance, increasing desirable bacterial species, and / or reducing undesirable bacteria). In some embodiments, the pathogen is a virus, bacteria, or fungus. In some embodiments, the pathogen is a respiratory disease virus, such as COVID-19, influenza, or respiratory syncytial virus. The fifth embodiment provides a method for assisting in the prevention and / or treatment of pathogen infection in an individual, or enhancing the therapeutic effect of pathogen infection in an individual, or improving the individual's immunity, or balancing the individual's gut microbiota (including increasing microbial abundance, increasing desirable bacterial species, and / or reducing undesirable bacteria), comprising administering to the individual a probiotic composition of the first embodiment, a prebiotic composition of the second embodiment, or a dietary composition of the third aspect. In some embodiments, the pathogen is a virus, bacteria, or fungus. In other embodiments, the pathogen is a respiratory disease virus, such as COVID-19, influenza, or respiratory syncytial virus.

Implementation Method

[0004] The inventors of this application have conducted extensive and in-depth research on gut microbiota, particularly probiotics, and have discovered a significant positive correlation between probiotics and ideal bacterial species that can enhance immunity and promote the prevention and treatment of pathogen infections (such as respiratory infections). Based on these findings, probiotic / prebiotic / synbiotic compositions are provided, which are expected to effectively enhance the body's immunity and help prevent and / or treat pathogen infections, such as respiratory pathogen infections, such as novel coronavirus (COVID-19), influenza, respiratory syncytial virus, etc. The content of this application is further elaborated below according to some specific embodiments. However, the specific embodiments listed are for illustrative purposes only and are not intended to limit the scope of this application. Those skilled in the art will recognize that a specific feature in one of the following embodiments can be used in any other embodiment, as long as it does not depart from the spirit of this application. Unless otherwise stated, the terms in this application have the same meaning as commonly understood by those skilled in the art. All patent documents, academic papers, and other published materials cited herein are incorporated herein by reference in their entirety. It should be understood that the specific numerical values ​​given herein should not only be interpreted as individual values, but also as providing endpoints for a range, and can be combined to provide other ranges. For example, when the content of a component of a composition is disclosed as 1, 2, or 3 g, it is equivalent to disclosing that the content of that component can be 1-2 g, 1-3 g, or 2-3 g. In a first embodiment, this application provides a probiotic composition comprising *Bifidobacterium bifidum* and *Bifidobacterium longum*. The term "probiotic composition" as used herein refers to a composition in which probiotics are the active ingredient, and does not exclude the presence of auxiliary components required for the cultivation, isolation, and purification of probiotics and / or excipients for formulating the composition according to the desired purpose. In some embodiments, the ratio of the amount of *Bifidobacterium bifidum* to *Bifidobacterium longum*, expressed in colony-forming units (CFU), is 1:(0.21-2.36). Colony-forming units (CFU) are a common form in the art for characterizing the quantity of microorganisms. Unless otherwise specified, the amount of microorganisms described in this application is calculated in colony-forming units. For example, the ratio of Bifidobacterium bifidum to Bifidobacterium longum may be 1:(0.21, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.36). In some embodiments, the composition is intended for administration to adults, and the ratio of Bifidobacterium bifidum to Bifidobacterium longum is 1:(0.36-2.36).In some embodiments, the composition is intended for children, with a ratio of Bifidobacterium bifidum to Bifidobacterium longum of 1:(0.21–1.7). In some embodiments, the probiotic composition also contains Bifidobacterium adolescentis. In some embodiments, the ratio of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum, in colony-forming units, is (0.57–3.56):1:(0.21–2.36). In some implementation samples, the ratios of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum were (0.57, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, ... 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.56):1:(0.21, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.36). In some specific formulations, the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*, in colony-forming units, is (0.75-1):1:(0.75-1). In some embodiments, the composition is administered to adults, and the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum* is (1-3.56):1:(0.86-2.36). In some embodiments, the composition was administered to children in a ratio of (0.57–3.09):1:(0.21–1.7) of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*. In some embodiments, the probiotic composition also included *Lactobacillus rhamnosus*. Short-chain fatty acids (SCFAs, such as butyrate and propionic acid) affect the differentiation or function of T cells, macrophages, and dendritic cells, which is significant for maintaining immune homeostasis. *Lactobacillus rhamnosus* can increase the production of SCFAs in the gut, and combinations of *Lactobacillus rhamnosus* with *Bifidobacterium bifidum* and *Bifidobacterium longum* are expected to increase total SCFA production. Furthermore, oral administration of *Lactobacillus rhamnosus* has been reported to increase the levels of *Bacteroides* and *Festuca* in the gut. In some implementation samples, the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum, and Lactobacillus rhamnosus was (0.57-3.56):1:(0.21-2.36):1.In some implementation samples, the ratios of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*, based on colony-forming units, were (0.57, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2) 7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.56):1:(0.21, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.36):1. In some embodiments, the composition is administered to adults in the following ratios: (1-3.56):1:(0.86-2.36):1. In some embodiments, the composition was administered to children, and the ratio of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus* was (0.57–3.09):1:(0.21–1.7):1. In some embodiments, the probiotic composition was in unit dose form, and the amounts of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus* were independently in the order of 10⁴ to 10¹² CFU. In some embodiments, the total amount of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus* was in the order of 10⁶ to 10¹² CFU. In some specific embodiments, the total amount of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus* was approximately 2 × 10¹¹ CFU. It should be understood that the probiotic composition of this application may not entirely contain *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*. Therefore, the "total amount" here refers to the total amount of these four probiotics present in the probiotic composition. The "unit dose form" described herein refers to a single-dose composition packaged individually or separately, typically in a single tablet, capsule, or powder / granule bag. In some embodiments, for ease of administration, the unit dose form is prepared as a composition containing a daily dose. In some embodiments, the probiotic composition is administered to adults, and the amount of *Bifidobacterium adolescentis* is 2.59 × 10⁵ - 4.49 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.26 × 10⁵ - 7.35 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 2.23 × 10⁵ - 7.02 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.26 × 10⁵ - 2.59 × 10¹¹ CFU.In some embodiments, the probiotic composition is intended for use in children, and the amount of *Bifidobacterium adolescentis* is 2.05 × 10⁵ - 4.55 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.47 × 10⁵ - 3.6 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 7.55 × 10⁴ - 2.5 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.47 × 10⁵ - 3.6 × 10¹¹ CFU. In some embodiments, the probiotic composition does not contain any probiotics other than those specified in the various embodiments of this application. In the context of such embodiments, "does not contain" should be understood as "substantially does not contain," but does not exclude the presence of trace or minute amounts of other probiotics due to factors such as the cultivation, isolation, and purification of the strains. In some specific embodiments, the amount of other probiotics accounts for no more than 5% of the total probiotic content of the composition, preferably no more than 1%. In some embodiments, the probiotic composition does not contain any probiotics other than *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Lactobacillus rhamnosus*. In some embodiments, the probiotic composition does not contain any Bifidobacterium other than *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum*. In a second embodiment, this application provides a prebiotic composition comprising xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. The term "prebiotic composition" as used herein refers to a composition in which prebiotics are the active ingredient, and does not exclude the presence of auxiliary components introduced during the synthesis, separation, purification, etc., of prebiotics, and / or excipients formulated according to the desired purpose. In some embodiments, the ratio of the amounts of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, by weight, is (0.25-5):(0.75-4):(0.5-1). In some embodiments, the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber by weight is (0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, ... 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0): (0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0): (0.5, 0.6, 0.7, 0.8, 0.9, 1.0).In some specific embodiments, the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber by weight is (0.25-0.5):(2-4):(0.5-0.75). In some embodiments, the prebiotic component is in unit dose form, and the total amount of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber by weight is 0.1-12g, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12g. In some embodiments, the prebiotic component is in unit dose form, with xylooligosaccharides ranging from 0.01g to 6g; and / or galactooligosaccharides ranging from 0.04g to 9.6g; and / or corn dietary fiber ranging from 0.01g to 6g. This unit dosage form can be given to adults or children. In some embodiments, when the prebiotic composition is used as a food supplement or additive, the total amount of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber can be controlled to be 0.1-5g, and the total amount after being combined with food is expected to reach the desired value, for example, about 12g. In some embodiments, the prebiotic composition does not contain prebiotic components other than xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. In the technical context of such embodiments, "free" should be understood as "substantially free," not excluding the presence of trace or ultra-trace amounts of other prebiotics due to factors such as the synthesis, extraction, separation, and purification of prebiotics. In some specific embodiments, the amount of other prebiotics accounts for no more than 5% of the total prebiotic amount of the composition, preferably no more than 1%. Thirdly, this application provides a dietary composition (sometimes also called a "synbiotics" composition) comprising the probiotic composition of the first embodiment and the prebiotic composition of the second embodiment. Those skilled in the art will understand that the aforementioned dietary composition does not need to be a separate formulation of the first-state probiotic composition and the second-state prebiotic composition, and then the two are mixed or combined. As long as a dietary composition covers all the characteristics of one embodiment of the first-state probiotic composition and all the characteristics of one embodiment of the second-state prebiotic composition, it belongs to the dietary composition of the third aspect of this application.As a non-limiting example, the dietary composition of this application may have the following formulation (daily dosage, which may be provided in unit dose form): In some specific embodiments, the dietary composition comprises Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum as probiotics, and xylooligosaccharides, galactooligosaccharides, and corn dietary fiber as prebiotics, wherein the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum, in terms of colony forming units (CFU), is (0.75-1):1:(0.75-1), and the total amount of the three bacteria is approximately 2×10¹¹ CFU, and the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, in terms of weight, is (0.25-0.5):(2-4):(0.5-0.75), and the total amount of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber is 1.2-1.5 g. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is formulated for oral administration. In some embodiments, oral administration includes oral administration, mixing with oral products, tube feeding, etc. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is a food supplement, food additive, or food. In some embodiments of the first to third aspects, the probiotic composition, prebiotic composition, or dietary composition is formulated as powder, granules, tablets, or capsules. The primary method of application for the probiotic composition, prebiotic composition, or dietary composition of this application is administration to the gastrointestinal tract of an individual. Direct oral administration is a convenient method, but for certain special individuals (e.g., bedridden patients), tube feeding or other methods may also be used as supplementary administration. The probiotic, prebiotic, or dietary components of this application can take many forms. For example, they can be prepared as standalone dietary supplements (e.g., capsules, tablets, powders, granules) to be taken with or without meals; they can also be prepared as additives added to or formulated into various solid / semi-solid foods, powder / granule foods, beverages, etc., before being ingested by an individual; or they can be used as direct components of various solid / semi-solid foods, powder / granule foods, and beverages. In some embodiments of the first to third aspects, the probiotic, prebiotic, or dietary components are administered to an individual to assist in the prevention and / or treatment of pathogen infections, or to enhance the therapeutic effect of pathogen infections, or to improve the individual's immunity, or to balance the individual's gut microbiota (including increasing microbial abundance, increasing desirable bacterial species, and / or reducing undesirable bacteria). In some embodiments, the pathogen is a virus, bacteria, or fungus. In some embodiments, the pathogen is a respiratory disease virus, such as COVID-19, influenza, or respiratory syncytial virus.The fourth embodiment of this application provides the use of probiotic components of the first embodiment, prebiotic components of the second embodiment, or dietary components of the third aspect in the preparation of dietary products or pharmaceuticals for assisting in the prevention and / or treatment of pathogen infections in individuals, or enhancing the therapeutic effect of pathogen infections in individuals, or improving the immunity of individuals, or balancing the gut microbiota of individuals (including increasing microbial abundance, increasing desirable bacterial species, and / or reducing undesirable bacteria). In some embodiments, the pathogen is a virus, bacteria, or fungus. In some embodiments, the pathogen is a respiratory disease virus, such as COVID-19, influenza, or respiratory syncytial virus. Where there is no conflict, the preparation of the probiotic components, prebiotic components, or dietary components of this application can refer to the conventional processing methods for probiotic or prebiotic products in the art. For example, various probiotic or prebiotic components can be mixed into the product sequentially or simultaneously or as a freeze-thaw mixture using conventional processing techniques. The fifth embodiment of this application provides a method for assisting in the prevention and / or treatment of pathogen infection in an individual, or enhancing the therapeutic effect of pathogen infection in an individual, or improving the individual's immunity or balancing the individual's gut microbiota (including increasing microbial abundance, increasing desirable bacterial species and / or reducing undesirable bacteria), comprising administering to the individual a probiotic composition of the first embodiment, or a prebiotic composition of the second embodiment, or a dietary composition of the third aspect. In some embodiments, the pathogen is a virus, bacteria, or fungus. In some embodiments, the pathogen is a respiratory disease virus, such as COVID-19, influenza, or respiratory syncytial virus. Examples The following examples are for illustrative purposes only and not for limiting the scope of this application. Example 1 This example describes a first-phase cohort study conducted by the inventors. Method Study Cohort 1 The inventors recruited 942 healthy Chinese individuals from Hong Kong (n = 61) and Yunnan Province (n = 881). This study was approved by the Joint Ethics Committee of Clinical Research in the Chinese University of Hong Kong-New Territories East Hospital Cluster (The Joint CUHK-NTEC CREC, CREC No.: 2016.407) and the Research Ethics Committee of the First Affiliated Hospital of Kunming Medical University (No.: 2017.L.14). All participants signed written informed consent forms. Fecal samples from the research subjects were stored at -80°C for bacteriological analysis. For Cohort 2, the inventors publicly recruited 546 healthy Hong Kong adults. This study was approved by the Joint Ethics Committee of Clinical Research in the Chinese University of Hong Kong-New Territories East Hospital Cluster (The Joint CUHK-NTEC CREC, CREC No.: 2016.707). All participants signed written informed consent forms, donated fecal samples, and provided demographic information through questionnaires. Fecal samples from the research subjects were stored at -80°C for bacteriological analysis. For Cohort 3, the inventors recruited 64 healthy children.This study was approved by the Joint Ethics Committee of the Chinese University of Hong Kong-New Territories East Hospital Cluster Clinical Research (The Joint CUHK-NTEC CREC, CREC No.: 2016.607). All participants signed written informed consent forms, donated stool samples, and provided demographic information through questionnaires. Stool samples from the study subjects were stored at -80°C for bacteriological analysis. Stool DNA extraction and sequencing for cohorts 1 and 3 were performed using Maxwell® RSC PureFood GMO and the Authentication Kit (Promega). Approximately 100 mg of each stool sample was pre-washed with 1 ml ddH2O and centrifuged at 13000g for 1 minute. The precipitate was resuspended in 800 μL LTE buffer (pH 7.5), 1.6 μL of 2-mercaptoethanol and 500 U of lyase (Sigma) were added, and the sample was incubated at 37°C for 60 minutes. The sample was then centrifuged at 13000g for 2 minutes, and the supernatant was discarded. After pretreatment, DNA was extracted using the Maxwell® RSC PureFood GMO and Authentication Kit (Promega) according to the product instructions. 1 ml of CTAB buffer was added to the pellet and vortexed for 30 s, then the solution was heated at 95°C for 5 min. Subsequently, the sample was homogenized with beads (Biospec, 0.5 mm for fungi, 0.1 mm for bacteria, 1:1) at high speed for 15 min. Then, 40 µl of proteinase K and 20 µl of RNase were added, and the mixture was incubated at 70°C for 10 min. The supernatant was then obtained by centrifugation at 13000 g for 5 min and transferred to a Maxwell® RSC instrument for DNA extraction. The extracted fecal DNA was used for ultra-deep metagenomic sequencing using an Ilumina Novoseq 6000 (Novogen, Beijing, China). An average of 12 G of data was obtained per sample. Fecal DNA extraction and sequencing for Cohort 2 were performed using the DNeasy PowerSoil Kit (QIAGEN) according to the manufacturer's instructions. DNA was extracted from 0.1g of fecal samples, and the concentration of the extracted DNA was determined using a Qubit dsDNA BR kit (Thermo Fisher Scientific). The DNA samples were sent to a sequencing service provider (Novogene HK Company Limited, Wan Chai, Hong Kong) for library preparation and paired shotgun metagenomic sequencing (Illumina NovaSeq 6000), with an average return of 7.5 GB of raw data per sample.Based on previous research by the inventors' team, the correlation analysis between bacterial species in this application revealed a negative correlation between various bacteria in the gut, including multiple Bacteroides and Bifidobacterium pseudocatenulatum, and the severity of COVID-19 or the viral load of SARS-CoV-2 in patients. This suggests that these bacterial species (referred to herein as "ideal bacterial species") have a protective effect against COVID-19 (related studies are described in U.S. Provisional Patent Applications 63 / 016,759 and 63 / 025,310, the contents of which are incorporated herein by reference in their entirety for all purposes). However, most of the ideal bacterial species are not currently approved for use in food. Therefore, the inventors conducted a correlation analysis between the bacterial species currently approved for use in food and the abundance of ideal bacterial species in the human population. Ideal bacterial species for correlation analysis include: Akkermansia muciniphila, Alistipes onderdonkii, Anaerostipes hadrus, Bacteroides dorei, Bacteroides massiliensis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bifidobacterium pseudocatenulatum, Eubacterium limosum, Eubacterium rectale, Eubacterium ventriosum, Faecalibacterium prausnitzii, Roseburia hominis, Roseburia intestinalis, and Eubacterium hallii. Correlation analysis was performed in study cohorts 1 and 2, as follows: Macro-genomic reads were quality filtered and pruned using preset parameters in Trimmomatic (v0.38). Then, host DNA (reference genome: hg38) was removed using Kneaddata (v0.7.2, https: / / bitbucket.org / biobakery / kneaddata / wiki / Home). Species-level metagenomic annotation was performed using MetaPhlAn26 (v2.6.0). Subsequently, the relative abundances generated by MetaPhlAn2 were subjected to a centered log ratio (clr) transformation.Pearson correlation coefficients were calculated and plotted using the R package corrplot v0.78. Results: In the correlation analysis of study cohorts 1 and 2, the relative abundance of some probiotic species was significantly correlated with the ideal bacterial species. Specifically, *Bifidobacterium bifidum*, *Bifidobacterium longum*, and *Bifidobacterium adolescentis* were positively correlated with several ideal bacterial species (Figure 1 and Table 1), suggesting that supplementation with these three probiotics can increase the abundance of at least some ideal bacterial species in the gut, improve gut health, and thus reduce the risk of infection or disease severity, such as enhancing immunity and preventing and treating respiratory infections. Probiotic proportions: The inventors calculated the average relative abundance of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum* in adults and children in study cohorts 1–3. These probiotic proportions are based on the natural proportions of various probiotics in healthy individuals, which were relatively constant in approximately 1500 healthy Chinese individuals in study cohorts 1–3. Therefore, simulating the proportions of species in healthy individuals may increase the chances of bacterial colonization in the gut. Based on this, the proportions of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum* in the synbiotic were designed as follows: adults (1-3.56):1:(0.86-2.36), and children (0.57-3.09):1:(0.21-1.7):1. The selection and proportion of prebiotics: Prebiotics and probiotics are usually complementary; therefore, after identifying and selecting probiotics, adding prebiotics to form a synbiotic is beneficial. For the types of probiotics identified in the above study, the inventors specifically selected prebiotics including xylooligosaccharides, galactooligosaccharides, and corn dietary fiber. Xylooligosaccharides, also known as xylooligosaccharides, refer to functional oligosaccharides composed of 2-10 xylose molecules linked by β-1,4 glycosidic bonds. Xylooligosaccharides are excellent bifidobacteria growth factors. Xylooligosaccharides have a very significant effect on the proliferation of *Bifidobacterium bifidum* and *Bifidobacterium adolescentis*. Reports indicate that *Bifidobacterium adolescentis*, *Bifidobacterium infantis*, and *Bifidobacterium bifidum* all utilize xylooligosaccharides by producing xylosidase and arabinosidase, and their hydrolytic ability for xylooligosaccharides depends on the efficiency of their xylanase enzymatic hydrolysis system. The proliferative effect of xylooligosaccharides on Bifidobacteria and the yield of short-chain fatty acids after fermentation decrease with increasing molecular weight of the xylooligosaccharide component. In vitro digestion experiments have shown that the residual rate of xylooligosaccharides after passing through saliva to the small intestinal mucosa enzyme solution reaches 99.6%, indicating that it can be fully fermented by Bifidobacteria in the large intestine, and the proliferative effect of xylooligosaccharides on Bifidobacteria is 10-20 times that of other functional oligosaccharides. Xylooligosaccharides have characteristics such as acid resistance, high temperature resistance, high stability, and good compatibility, making them well-suited for food applications. Galacto-oligosaccharides and corn dietary fiber can promote the growth of various Bifidobacteria. Galacto-oligosaccharides are a novel functional substance, whose molecular structure generally consists of 1-7 galactose groups linked to galactose or glucose molecules. It is a type of functional oligosaccharide with natural properties.It has good palatability, water solubility, and stability. After entering the human body, it can promote the proliferation of beneficial bacteria, especially Bifidobacteria, in the human gut, while also inhibiting the growth of putrefactive bacteria. The beneficial bacteria in the gut utilize galactooligosaccharides for proliferation and also produce a large amount of extracellular polysaccharides. These extracellular polysaccharides not only have anti-tumor and immune-enhancing activities but also promote the long-term colonization of beneficial bacteria in the gut. After entering the stomach, corn dietary fiber can absorb some water and promote intestinal peristalsis, accelerating the excretion of feces, thereby reducing rectal pressure and preventing and reducing intestinal diseases. Simultaneously, Bifidobacteria have a fermentation effect on corn dietary fiber, allowing it to be rapidly fermented by microorganisms in the cecum to produce short-chain fatty acids. Based on the proportion of probiotics, the inventors further provided a suitable ratio of three prebiotics, where the ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber can be (0.25-5):(0.75-4):(0.5-1). Example 2 This example describes an extended second-phase cohort study conducted by the inventors based on research cohort 2 of Example 1. Methods Study Cohort HC (i.e., Study Cohort 2 of Example 1) For fecal samples of the study subjects, fecal DNA extraction was performed using the QIAamp DNeasy PowerSoil kit according to the manufacturer's instructions. Study Cohort CR1 The inventors publicly recruited 219 healthy Hong Kong adults. This study was approved by the Joint CUHK-NTEC CREC (CREC No.: 2017.369). All subjects signed written informed consent, donated fecal samples, and provided demographic information through questionnaires. Fecal samples of the study subjects were stored at -80°C for bacteriological analysis. Fecal DNA extraction was performed using the QIAamp DNA Stool Mini kit according to the manufacturer's instructions. Study Cohort CR2 The inventors randomly selected fecal samples from 30 healthy Hong Kong adults who underwent colonoscopy and had normal results from a cohort of asymptomatic subjects. This study was approved by the Joint Ethics Committee for Clinical Research of the Chinese University of Hong Kong-NTEC Network of Hospitals (The Joint CUHK-NTEC CREC, CREC No.: 2017.198). All participants signed written informed consent forms to donate stool samples. Stool samples from the study object were stored at -80°C prior to microbiome analysis. Stool DNA extraction was performed using the Maxwell RSC PureFood GMO and Authentication kit, following the manufacturer's instructions. The study cohort enrolled stool samples from 78 healthy Hong Kong adults from a healthy control group in a COVID-19 study.Fecal DNA extraction was performed using the Maxwell RSC PureFood GMO and Authentication kit, according to the manufacturer's instructions. The inventors randomly selected 67 healthy Hong Kong adults with a BMI <23 from the LeanHC study cohort. Fecal samples from these study subjects were stored at -80°C for microbiome analysis. Fecal DNA extraction was performed using the Maxwell RSC PureFood GMO and Authentication kit, according to the manufacturer's instructions. Fecal Samples and DNA Extraction This example includes fecal samples collected from healthy subjects from five independent cohort studies. Fecal DNA extraction was performed using the QIAamp DNeasy PowerSoil kit, the Maxwell RSC PureFood GMO and Authentication kit, or the QIAamp DNA Stool Mini kit, according to the manufacturer's instructions. The quality and quantity of DNA were determined using a NanoDrop spectrophotometer and gel electrophoresis. Metagenomic Sequencing DNA libraries were constructed through end repair, purification, and PCR amplification. After constructing the DNA library, it was sequenced using a 150bp paired-end sequencing strategy on the NextSeq platform in the inventors' laboratory. An average of 12Gb of data was obtained per sample for further analysis. All experimental procedures were performed according to the inventors' laboratory's standardized procedures. For data processing and statistical analysis of the macro-genomics data, the inventors used Fastp to perform quality filtering, PolyG tail modification, and translepton modification on the sequenced fragments of the metagenomics, and deleted sequences of 50 bases or less. Then, KneadData was used to remove human genes from the quality-pruned metagenomic sequences, and MetaPhlAn2 was used to analyze the species-level metagenomics; all non-zero levels were considered positive. The inventors calculated the incidence of each species and its combinations. The inventors used Pearson correlation analysis to explore the correlation between species level and age and sex. The correlation between species level and age was analyzed using Pearson correlation, and the correlation between species level and sex was assessed using Spearman correlation. In the overall analysis of the above-mentioned healthy cohort, the positive rates of *Bifidobacterium adolescentis*, *Bifidobacterium bifidum*, and *Bifidobacterium longum* were 68.2%, 20.3%, and 81.7%, respectively (see Figure 2, A). Less than 20% of the healthy subjects had all three bifidobacterial species in their gut, 46.3% had two of the three species, and a high percentage (36.3%) had only one of the three species or none at all (see Figure 2, B).The inventors further analyzed the correlation between the levels of the three Bifidobacterium species and age and sex. The results showed a negative correlation between increasing age and all three Bifidobacterium species. Male sex was significantly correlated with low levels of *Bifidobacterium longum* (Table 2). These results suggest that supplementation with the probiotic / prebiotic / synbiotic composition of this application is suitable for most populations, especially older individuals and men. Example 3 This example describes the effect of administering the synbiotic composition of this application on symptom improvement and modulation of immune response markers in hospitalized COVID-19 patients. Coronavirus disease-2019 (COVID-19), caused by the SARS-CoV-2 virus, has been reported to affect not only the lungs but also multiple other organs, including the gut. Gut microbiota can modulate the host's immune response and therefore may influence the severity and prognosis of COVID-19 patients. The gut microbiome of COVID-19 patients becomes imbalanced, with reduced symbionts and increased opportunistic pathogens, both of which are associated with COVID-19 severity and fecal SARS-CoV-2 virus shedding. Furthermore, reports indicate that higher levels of probiotics producing short-chain fatty acids in fecal samples are associated with lower SARS-CoV-2 infectivity, highlighting the potential beneficial role of beneficial bacteria in combating SARS-CoV-2 infection. Treatment regimens that rebalance the gut microbiome in COVID-19 patients have the potential to improve clinical outcomes. The inventors anticipated that the synbiotic composition of this application would improve the clinical symptoms of COVID-19 patients and therefore designed and conducted a preliminary study to evaluate the effects of this synbiotic composition on the clinical symptoms, blood immune markers, and fecal microbiome of COVID-19 in hospitalized COVID-19 patients. The inventors compared these results with those of hospitalized COVID-19 patients receiving standard treatment during the same period (control group). The formulation of the synbiotic composition used in this study is as follows: The synbiotic composition contains Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum as probiotics, and xylooligosaccharides, galactooligosaccharides, and corn dietary fiber as prebiotics. The ratio of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum, in terms of colony forming units (CFU), is controlled at (0.75-1):1:(0.75-1), and the total amount of the three bacteria is controlled at approximately 2×10¹¹ CFU. The ratio of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber, in terms of weight, is controlled at (0.25-0.5):(2-4):(0.5-0.75), and the total amount of xylooligosaccharides, galactooligosaccharides, and corn dietary fiber is controlled at 1.2-1.5g. Study Overview: The inventors enrolled adult patients who tested positive for SARS-CoV-2 at Prince of Wales Hospital between August 13, 2020 and October 9, 2020. Enrolled COVID-19 patients received standard treatment or the synbiotic composition of this application within 48 hours of admission.Subjects received standard treatment or took synbiotic capsules for 28 days. The primary outcome was a comprehensive assessment of three indicators: the overall symptom questionnaire assessing symptom relief, the need for respiratory support, and antibody production from the start of treatment to week 5. Questions 1-19 and 26 of the overall symptom questionnaire (Table 3) assessed COVID-19-related symptoms, including fever, respiratory symptoms, and general symptoms, with a minimum score of 20 (normal) and a maximum score of 80 (most severe symptoms). A score of 20 was awarded for complete symptom relief. Questions 20-25 of Table 3 assessed gastrointestinal (GI) symptoms, with a score of 6 for complete GI symptom relief. SARS-CoV-2 immunoglobulin G (IgG) antibody testing was performed within 2 weeks of hospital admission. The inventors assessed patients' clinical symptoms every two days until symptoms disappeared or the patient was discharged. The inventors also included another group of patients receiving standard treatment at the same time for comparison. In all subjects, the inventors collected blood samples at baseline and 5 weeks after taking the synbiotic composition, and used the MILLIPLEX® MAP immunoassay to detect immune response markers in plasma at baseline and week 5 in both the standard treatment group and the synbiotic group. The inventors also collected stool samples and quality of life questionnaires at baseline and at weeks 2, 4, and 5 after taking the synbiotic composition. Methods and Subject Recruitment: This study was approved by the Joint CUHK-NTEC CREC (CREC Ref. No: 2020.407) and registered with the Clinical Trials Registry (NCT04581018). All subjects provided written informed consent. Enrolled subjects included 25 subjects in the synbiotic composition group and 30 subjects in the standard treatment group (SC). The inventors recruited patients aged 18 years or older who were diagnosed with SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction (PCR) test and hospitalized at Wales Hospital, Hong Kong, between August 13 and October 9, 2020. Subjects receiving intensive care or on a ventilator, those allergic or intolerant to the intervention product or its components, those with a known history of endocarditis or active endocarditis, those who had recently undergone CAPD or hemodialysis, or those who were pregnant at the time of recruitment were excluded. Subjects with any condition that would prevent oral administration of probiotics or increase the risk associated with probiotics were also excluded. These risks include, but are not limited to, inability to swallow or risk of aspiration without other methods of administration (e.g., no G / J tube), known increased risk of infection due to immunosuppression, such as a history of organ or hematopoietic stem cell transplantation, neutropenia (ANC <500 cells / μl), or HIV and CD4 <200 cells / μl. Subjects hospitalized between August and October 2020 were assigned to either the synbiotic formulation group or the standard treatment group.Participants discharged in July 2020 were assigned to the standard treatment group. In this study, participants took the synbiotic capsules with food for 28 days as directed, and clinical symptoms were assessed every two days until symptom resolution or discharge. Blood samples were collected at baseline and 5 weeks after the first dose of the synbiotic or enrollment. Stool samples and quality of life questionnaires were collected at baseline and weeks 2, 4, and 5 after the first dose of the synbiotic or enrollment. This study was conducted in accordance with the Declaration of Helsinki. For blood immunomarkers, whole blood samples were centrifuged at 1500 x g for 10 minutes without braking at 4°C after standing for 60 minutes to collect plasma. Undiluted plasma was transferred to 15 mL polypropylene conical tubes, aliquoted, and stored at -80°C for subsequent studies. Plasma cytokine and chemokine levels were detected using a Custom Premix Human Cyto Panel A 47 Plex (Millipore, #HCYTA-60K-47C). All samples were tested upon first thawing. Results: This study included 25 COVID-19 patients who took the synbiotic formulation and 30 patients who received standard treatment. Patient clinical characteristics are shown in Table 3. There were no significant differences in age, comorbidities, baseline symptom scores, and disease severity between the two groups. At diagnosis, vital signs, hypoxemia, and inflammatory markers were similar between the two groups (data not shown). Compared with the standard treatment group, the proportion of patients achieving complete symptom relief was significantly higher in the synbiotic formulation group (Figure 3, A, Week 1: 64% vs 10%; p = <0.001; Week 2: 100% vs 52%; p <0.001), and the antibody positivity rate was also significantly higher (Day 16: 88% vs 63%; p = 0.037). Eight subjects (26.7%) in the standard treatment group and one subject (4%) in the synbiotic formulation group never tested positive for IgG antibodies before discharge. All patients receiving the synbiotic formulation experienced relief of gastrointestinal (GI) symptoms by Week 2 (Figure 3, A). Assessing quality of life using the EuroQol Visual Analogue Scale (EQ-VAS) and EuroQol Index Score (EQ Index Score) (specific data not shown), subjects in the synbiotic formulation group showed a significant improvement in quality of life at week four compared to baseline (EQ-VAS week four and baseline scores were 81.5 and 69.75, respectively, p = 0.034; EQ Index Score at week four and baseline were 0.839 and 0.805, respectively, p < 0.0005), but no such improvement was observed in the standard treatment group. No serious adverse events were observed in either group. Several adverse events were observed in the synbiotic formulation group, including mild dizziness (4%), tinea infection (4%), and hypertension (4%). One subject (4%) was diagnosed with chronic lymphocytic leukemia through routine blood tests.In the standard treatment group, 3 subjects (10%) experienced constipation, and 1 subject (3.3%) experienced mild hand inflammation. In the synbiotic formulation group, eight major immunomodulatory markers—interleukins (IL-6, IL-1RA, IL-18), tumor necrosis factor (TNF-α), macrophage colony-stimulating factor (M-CSF), CXC chemokine ligand 10 (CXCL-10, also known as IP10), monocyte chemoattractant protein 1 (MCP-1), and interferon-γ-induced monokinetic factor (MIG)—were significantly reduced at week 5 compared to their baseline counterparts. Conversely, in the standard treatment group, many of these immunomodulatory markers showed no significant changes (Figure 3, B). The percentage decreases in IL-6, CXCL-10, IL-1RA, MIG, TNF-α, and M-CSF at week 5 compared to baseline were significantly greater in the synbiotic formulation group than in the control group (Figure 3, C). In the synbiotic composition group, the abundance of *Bifidobacterium adolescentis* and *Bifidobacterium longum* significantly increased compared to baseline at weeks 2 and 5 (Figure 3, D). This preliminary study found that in hospitalized COVID-19 patients, use of the synbiotic formulation of this application reduced gastrointestinal symptoms and suppressed inflammatory cytokine levels. The theoretical basis of this study is that the use of the synbiotic composition in COVID-19 patients can rebalance the gut microbiome, thereby reducing disease severity and improving quality of life. Prior data on the anti-SARS-CoV-2 effects of synbiotics in COVID-19 patients is limited. The inventors are the first to discover that the gut of COVID-19 patients lacks a range of beneficial bacteria and that viral infection and replication persist in the gut even after the respiratory tract clears the SARS-CoV-2 virus. Using big data analysis and machine learning, the inventors developed a probiotic formulation targeting gut microbiota imbalance. In the synbiotic composition group, the abundance of probiotics increased significantly at week 2, confirming successful delivery of probiotics to the gut. Studies showed elevated levels of immune response markers in severely ill COVID-19 patients, including IL-6, IL-1RA, IL-18, TNF-α, M-CSF, CXCL10, MCP-1, and MIG. The inventors found that the synbiotic composition could reduce the levels of these eight immune response markers in plasma samples at week 5. Simultaneously, COVID-19 symptoms in patients were alleviated at weeks 2 and 5 after synbiotic composition treatment. These results suggest that synbiotic composition treatment may enhance the host's immune response to SARS-CoV2, primarily by suppressing the elevated cytokines in the early stages of COVID-19 infection. This finding provides a basis for targeted therapy using synbiotics against the gut microbiota.The inventors' research suggests that synbiotics have an early immune intervention effect, providing a reference and hope for using synbiotic components to enhance the body's immunity in combating COVID-19 and other emerging viral infections. Example 4: This example is an extension study based on Example 3. The inventors included 25 COVID-19 patients who took the synbiotic component and 10 patients who received standard treatment from Example 3. In addition, the inventors included 69 patients who received standard treatment and 78 healthy individuals as a control group. Through metagenomic analysis, it was found that the synbiotic formula of this application can restore the imbalanced gut microbiota to a balanced state, reaching or approaching the level of normal individuals. Research Methods: Subject Recruitment: The inventors included 25 COVID-19 patients who took the synbiotic component and 10 patients who received standard treatment from Example 3. In addition, the inventors included 69 patients who received standard treatment. This study was approved by the Joint CUHK-NTEC CREC (CREC Ref. No: 2020.076) and conducted in accordance with the Declaration of Helsinki. All participants signed written informed consent forms. These COVID-9 patients were recruited from Prince of Wales Hospital and United Christian Hospital in Hong Kong between February and May 2020. Nasopharyngeal swabs were collected from these patients by hospital staff and confirmed by laboratory testing using quantitative reverse transcription polymerase chain reaction (RT-qPCR) to be positive for SARS-CoV-2. The inventors also included 78 healthy individuals as a control group from a Hong Kong population gut microbiome survey study, recruited through advertising or colonoscopy trials. Stool sample collection is described in Figure 4. The inventors collected stool samples from participants in the synbiotic composition and standard treatment groups at different time points (baseline, week 2, 4, and 5). Additionally, the inventors collected stool samples from the healthy control group at one time point. Fecal samples and DNA extraction were performed according to the manufacturer's instructions using the QIAamp DNeasy PowerSoil kit, Maxwell RSC PureFood GMO and Authentication kit, or QIAamp DNA Stool Mini kit. DNA quality and quantity were determined using a NanoDrop spectrophotometer and gel electrophoresis. Metagenomic sequencing was performed to construct the DNA library through end repair, purification, and PCR amplification. After library construction, the DNA library was sequenced using a 150bp paired end sequencing strategy on the NextSeq platform in the inventor's laboratory. An average of 12Gb of data was obtained per sample for further analysis. All experimental procedures were performed according to the inventor's laboratory's standardized procedures.Data processing and statistical analysis of macro-genomics data used Fastp to perform quality filtering on the metagenomic sequences, PolyG tail modification and translepton modification, and deleted sequences of 50 bases or less. Then, KneadData was used to remove human genes from the quality-pruned metagenomic sequences, and MetaPhlAn2 was used to analyze the species-level metagenomics; all non-zero levels were considered positive. The inventors calculated the incidence of each species and its combinations. As described in Example 1, based on the inventors' previous research, species in the gut, including various Bacteroides and Bifidobacterium pseudocatenulatum, that showed a negative correlation with the severity of COVID-19 disease or SARS-CoV-2 viral load were defined as "ideal bacterial species" (related studies are described in U.S. Provisional Patent Applications 63 / 016,759 and 63 / 025,310). Species with relatively high abundance in the gut of COVID-19 patients were defined as "unideal bacterial species." The Shannon diversity index (α-biodiversity index) was calculated using the Vegan package in the R software. Microbiome differences were analyzed using the LEfSe software (linear discriminant analysis [LDA] effect size). Species with an LDA greater than 2 and p < 0.05 were considered statistically significant between groups. Compared to baseline, the total abundance of the three Bifidobacterium species in the synbiotic formulation of this application slightly decreased in COVID-19 patients receiving standard treatment at weeks 2 and 4; in contrast, the total abundance of the three Bifidobacterium species significantly increased in patients receiving the synbiotic composition at weeks 2 and 4 (Figure 5). Compared to baseline, the Shannon diversity index significantly decreased in COVID-19 patients receiving standard treatment at weeks 2, 4, and 5; in contrast, the Shannon diversity index remained at a similar high level as at baseline in COVID-19 patients receiving the synbiotic composition (Figure 6). In COVID-19 patients receiving standard treatment, the total abundance of ideal bacterial species was significantly reduced at weeks 2 and 4 compared to baseline; in contrast, in COVID-19 patients receiving synbiotic formulations, the total abundance of ideal bacterial species was significantly increased at weeks 2 and 4 compared to baseline (Figure 7, A). Simultaneously, at weeks 2, 4, and 5 compared to baseline, the total abundance of undesirable bacterial species was significantly reduced in COVID-19 patients receiving synbiotic formulations, while no reduction was observed in patients receiving standard treatment (Figure 7, B).Furthermore, compared to COVID-19 patients receiving standard treatment, COVID-19 patients receiving synbiotic formulations showed a significantly higher abundance of desirable bacterial species, including *Bifidobacterium adolescentis*, *Eubacterium rectum*, *Ruminococcus*, and *Bifidobacterium longum* (Figure 8). Exemplary embodiments of the inventions described above have been described. However, without departing from the spirit and scope of this application, those skilled in the art can modify or improve the exemplary embodiments described herein, and the resulting variations or equivalents also fall within the scope of this application. [Simplified Explanation of the Diagram]

[0005] [Figure 1] shows the relationship between the ideal bacterial species identified in previous studies and various probiotics. The ideal bacterial species have the potential to enhance immunity, and their abundance is negatively correlated with the severity of COVID-19 disease or the viral load of SARS-CoV-2. Circles represent a positive correlation between the abundance of the ideal bacterial species and probiotics, with the size indicating the strength of the positive correlation. The boxes enclose the target probiotics identified in this application. [Figure 2] shows some results of the cohort study of Example 2, where Figure A shows the positivity rates of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum in each cohort study and the overall positivity rate; Figure B shows the incidence of the presence of any two of the three Bifidobacteria, or only one of the three Bifidobacteria, or no Bifidobacterium in the fecal samples of the subjects. [Figure 3] shows partial results from the clinical study of Example 3 in COVID-19 patients treated with the synbiotic composition and standard therapy. Figure A shows the clinical symptom relief scores (defined as 20) and antibody formation at weeks 1 and 2; Figure B shows the quantification of immune response markers in plasma (converted to log10 for display). For all box plots, the center is plotted using the measured median, and the upper and lower boundaries of the box plots correspond to the first and third percentiles, respectively. The p-value was determined by two-sided Wilcoxon rank-sum test, and a p-value < 0.05 was considered statistically significant; Figure C shows the percentage decrease in inflammatory immune response markers at week 5 compared to baseline, with each bar representing the median percentage decrease. The p-value was determined by two-sided Wilcoxon rank-sum test; Figure D shows the probiotic concentrations at baseline, 2 weeks after the first administration of the synbiotic composition, and 5 weeks after administration. The concentrations were determined by qPCR and displayed after log10 conversion (ng / μl). A p-value < 0.05 was considered statistically significant (Wilcoxon rank-sum test). [Figure 4] shows the study design of Example 4. [Figure 5] shows the total relative abundance of three Bifidobacterium species (Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum) in the synbiotic composition in healthy individuals and COVID-9 patients in the synbiotic composition group and standard treatment group at baseline, week 2, 4, and 5 in Example 4. The upper figure is a summary figure, and the lower figure is a figure for each time point. Relative abundance (percentage) is shown in log10 format. The p-values ​​between the relative abundance at week 2, 4, and 5 and baseline were determined by Wilcoxon rank-sum test. [Figure 6] shows the Shannon diversity index in healthy individuals and COVID-9 patients in the synbiotic composition group and standard treatment group at baseline, week 2, 4, and 5 in Example 4. The p-values ​​between the Shannon diversity index at week 2, 4, and 5 and baseline were determined by Wilcoxon rank-sum test.[Figure 7] shows the total relative abundance of ideal bacterial species (A) and undesirable bacterial species (B) in healthy individuals and COVID-9 patients in the synbiotic composition group and standard treatment group at baseline, weeks 2, 4, and 5 in Example 4. Figure A shows the total relative abundance of ideal bacterial species (species with higher abundance in non-COVID-19 individuals), and Figure B shows the total relative abundance of undesirable bacterial species (species with higher abundance in COVID-19 patients). Relative abundance (percentage) is shown in log10 form. The p-values ​​between relative abundance at weeks 2, 4, and 5 and baseline were determined by Wilcoxon rank-sum test. [Figure 8] shows the species with different abundance between the synbiotic composition group and standard treatment group in Example 4 at baseline, weeks 2, 4, and 5 (LDA > 2, p < 0.05). Compared to the standard treatment group, the levels of several desirable bacterial species (marked with boxes) were significantly higher in the synbiotic composition group, while the levels of undesirable bacterial species (Klebsiella pneumoniae, Veillonella spp., and Escherichia coli) were significantly lower in the synbiotic composition group than in the standard treatment group. The relationship between box color intensity and LDA values ​​is illustrated in the figure. A positive LDA value indicates a significantly higher level of the species in the synbiotic composition treatment group, with darker colors representing greater differences. A negative LDA value indicates a significantly higher level of the species in the standard treatment group, with lighter colors representing greater differences.

Claims

1. The use of a probiotic composition for manufacturing a medicament for enhancing the treatment of an individual with SARS-CoV-2 (COVID-19), the probiotic composition comprising Bifidobacterium bifidum, Bifidobacterium longum and Bifidobacterium adolescentis.

2. The use as described in claim 1, wherein the ratio of the amount of Bifidobacterium bifidum to Bifidobacterium longum, in colony-forming units, is 1:(0.21-2.36).

3. The use as described in claim 1, wherein the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum and Bifidobacterium longum, in colony-forming units, is (0.57-3.56):1:(0.21-2.36).

4. The use as described in claim 1, wherein the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum and Bifidobacterium longum, in colony-forming units, is (0.75-1):1:(0.75-1).

5. For the purposes described in any of claims 1-4, it also includes Lactobacillus rhamnosus.

6. The use as described in claim 5, wherein the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum and Lactobacillus rhamnosus, in colony-forming units, is (0.57-3.56):1:(0.21-2.36):

1.

7. The use as described in claim 5, wherein the probiotic composition is in unit dose form and the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum, and Lactobacillus rhamnosus are independently in the range of 10⁴ to 10¹² CFU per colony-forming unit.

8. The use as described in claim 5, wherein, The total amount of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum, and Lactobacillus rhamnosus is in the range of 10⁶ to 10¹² CFU.

9. The use as described in claim 5, wherein the probiotic composition is intended for administration to adults, and the amount of *Bifidobacterium adolescentis* is 2.59 × 10⁵–4.49 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.26 × 10⁵–7.35 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 2.23 × 10⁵–7.02 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.26 × 10⁵–2.59 × 10¹¹ CFU.

10. The use as described in claim 5, wherein the probiotic composition is intended for use in children, and the amount of *Bifidobacterium adolescentis* is 2.05 × 10⁵–4.55 × 10¹¹ CFU; and / or the amount of *Bifidobacterium bifidum* is 1.47 × 10⁵–3.6 × 10¹¹ CFU; and / or the amount of *Bifidobacterium longum* is 7.55 × 10⁴–2.5 × 10¹¹ CFU; and / or the amount of *Lactobacillus rhamnosus* is 1.47 × 10⁵–3.6 × 10¹¹ CFU.

11. The use as described in any one of claims 1-4, wherein the probiotic composition does not contain any Bifidobacterium other than Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum.

12. The use as described in claim 11, wherein the probiotic composition does not contain any probiotics other than Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium longum, and Lactobacillus rhamnosus.

13. The use as described in any one of claims 1-4, wherein the probiotic composition further comprises xylose oligosaccharides, galactose oligosaccharides and corn dietary fiber.

14. The use as described in claim 13, wherein the ratio of the amounts of xylose oligosaccharide, galactose oligosaccharide and corn dietary fiber, by weight, is (0.25-5):(0.75-4):(0.5-1).

15. The use as described in claim 14, wherein the ratio of the amounts of xylose oligosaccharide, galactose oligosaccharide and corn dietary fiber, by weight, is (0.25-0.5):(2-4):(0.5-0.75).

16. The use as described in claim 13, wherein the probiotic composition is in unit dose form and the total amount of the xylose oligosaccharides, galactose oligosaccharides and corn dietary fiber is 0.1-12 g by weight.

17. The use as described in claim 16, wherein, The total amount of xylose oligosaccharides, galactose oligosaccharides and corn dietary fiber is 0.1-5g by weight.

18. The use as described in claim 16, wherein the amount of xylose oligosaccharides is 0.01g-6g; and / or the amount of galactose oligosaccharides is 0.04g-9.6g; and / or the amount of corn dietary fiber is 0.01g-6g.

19. The use as described in claim 13, wherein the probiotic composition does not contain xylose oligosaccharides, galactose oligosaccharides, or prebiotic components other than corn dietary fiber.

20. The use as described in any one of claims 1-4, wherein the probiotic composition is a dietary composition, and wherein the dietary composition comprises Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum as probiotics and xylose oligosaccharides, galactose oligosaccharides, and corn dietary fiber as prebiotics, wherein the ratio of the amounts of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum, in colony-forming units (CFU), is (0.75-1):1:(0.75-1), and the total amount of the three bacteria is 2×10¹¹ CFU, and the ratio of xylose oligosaccharides, galactose oligosaccharides, and corn dietary fiber, in weight, is (0.25-0.5):(2-4):(0.5-0.75), and the total amount of xylose oligosaccharides, galactose oligosaccharides, and corn dietary fiber is 1.2-1.5 g.

21. The use as described in claim 20, wherein the dietary component is formulated for oral administration.

22. The use as described in claim 20, wherein the dietary component is a food supplement, food additive, or food.

23. The use as described in claim 20, wherein the dietary ingredient is formulated as a powder, granules, tablet or capsule.

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