Research Advances and Application Prospects of Lactic Acid Bacteria Fermentation of Chinese Herbal Medicines

China is the birthplace of Chinese medicine. Ancient physicians not only proved the remarkable pharmacological activity of Chinese medicines, but also constructed a complete theoretical system of Chinese medicines by systematically observing the natural physical properties of Chinese medicines and combining them with the verification of real cases over thousands of years. Though Chinese Herb Medicines (CHM) have a wide variety of ingredients, the content of their active ingredients is generally low. For example, researchers have determined the content of each component in Scutellarin baicalinase’s by high performance liquid chromatography (HPLC), The findings of the tests show that: In a sample of Scutellaria baicalensis, baicalein was present at about 20 mg/g. Baicalein was relatively high among the various constituents, but its content was only about one hundred milligrams per gram of Scutellaria baicalensis. Wild baicalin was lower, with less than 2 mg/g per gram, however, there were other constituents that contained less than it [1]; Similarly, another study measured the saponins in ginseng by HPLC-ELSD, in which the mean aggregate amount of eight saponins (including ginsenoside Rg₁, ginsenoside Rb₁, ginsenoside Rb₂, ginsenoside Rf, etc.) were ranging from 7.10 to 12.75 mg/g, and the mean total amount of seven nucleosides (thymine, adenine, cytosine, thymosine, adenosine, guanosine, Uridine) had an average total content of less than 1 mg/g [2]. Therefore, the first and foremost prerequisite for achieving the full efficacy of CHM is to enhance the content of the active ingredients of them.

The fermentation treatment of CHM usually results in a significant increase in the content of active ingredients, and the pharmacological activity of most fermented herbs is superior to that of the unfermented raw material [3, 4]. Lactic Acid Bacteria (LAB) have a long history of usage in human society, and in the field of CHM fermentation, LAB, as the most widely used probiotic genus, is gradually becoming the focus of research and industrial application. During the fermentation of CHM, LAB, with its rich enzyme system, is able to decompose the cell wall and intercellular components of CHM, which not only improves the flavor and taste of CHM, but also improves its bioavailability and enhances the therapeutic effect [5]. Some studies on LAB fermentation have shown good improvement in the efficacy of CHM, e.g. the antioxidant capacity of goldenseal was improved after LAB fermentation and the average antioxidant capacity of its roots, stems and leaves could reach 61%- 78% [6]; Similarly, the metabolites of ginsenosides increased from 4637.0 μg mL ^-1 to 7581.1 μg mL ^-1 after 4 d after fermentation of red ginseng Koryo ginseng by LAB, and their immunological activities were also increased [7]. In another study on the fermentation of Scutellaria baicalensis by LAB, it was found that LAB was able to promote the conversion of baicalin to baicalein in it, as well as causing the conversion of Wogonoside to Wogonin. The result of this conversion helped to enhance the antimicrobial activity and antioxidant capacity of Scutellaria baicalensis extract [8]. 

Although LAB have been widely used in the field of fermentation, however, the current mechanism of the interaction between LAB and CHM is still unclear, the metabolic pathway is still unclear, and the related research mostly stays in the laboratory exploration stage, while the scale-up production process is not mature enough, and at the same time, the taxonomic system of LAB has not yet been completely established and perfected. To a certain extent, these problems have restricted the popularization, application and further development of LAB fermentation technology in a wider field. Therefore, a systematic and comprehensive analysis of LAB fermentation of CHM is particularly necessary. This paper summarizes and discusses the current research status of lactobacilli fermentation of herbal medicine and discusses the future development of lactobacilli fermentation, aiming to provide a useful reference for the subsequent research and industrial development in this field.

As of 2019, a total of 35 species or subspecies of microorganisms have been approved as edible probiotics in China [9]. By 2022, for the ‘List of strains that can be used in food’ and the ‘List of strains that can be used in food for infants and young children, the National Health Council has issued an updated public notice circular, The announcement indicated the addition of 16 new food-usable strains and adjusted the names of some strains, most of the updates related to LAB. 

LAB are a group of Gram-positive cells without spores, and their main metabolic end-product is lactic acid. According to Berry's bacteriological and biochemical classification, they can be divided into the genera Lactobacillus, Bifidobacterium, Streptococcus, Streptococcus, Streptococcus and Schizococcus, LAB play an important role in food microbiology and human nutrition and it is considered one of the most essential bacteria in human society [10]. The species of lactic acid bacteria commonly used in fermentation today are listed (Table 1).

Table 1: Commonly used lactic acid bacteria strains for fermentation. 

Currently, the one-to-one model of LAB and CHM is still dominant in the fermentation practice of CHM, while there is a relative lack of research on the fermentation of single or multiple CHM using multiple LAB. Some LAB are widely used in other fields such as food and feed, but its potential in the field of CHM fermentation has not yet been fully explored, and still has a broad development prospect. It is expected to bring better results for CHM fermentation by screening new LAB strains or constructing new LAB colony structures.

The fermentation of LAB is mainly carried out through the glycolysis pathway, and during the fermentation and metabolism process, a variety of extracellular and intracellular enzymes are released, which play unique roles (Figure 1). 

The enzymes, such as cellulase and pectinase, can act on the cell wall and change the permeability of it, thus making it easier for the active substances to be dissolved, and thereby increasing the utilization rate [58]. For example, when the roots, stems and leaves of astragalus were fermented using Streptococcus lactis, the cellulose in the plant could be degraded, and the results showed that the contents of crude polysaccharides, total flavonoids and total saponins were significantly increased [59]. In addition, enzymes like glycosidases and proteases are capable of triggering structural modification reactions by acting on specific substrate molecules. Glycosidases have the ability to hydrolyze glycosidic bonds and increase glycosidic content through deglycosylation reactions. For example, during the fermentation of astragalus by Lactobacillus plantarum, β-glucosidase is able to catalyse the hydrolysis of the glycosidic bond of flavonoid glycosides, which leads to the conversion of Calycosin glucoside to Lupalosin glucoside, and at the same time realises the conversion of Lupalbigenin to Formonetin [60]; In addition, other similar enzymes have also been studied. In the system of LAB fermented Lycium barbarum, the activity of pectinase was significantly increased, which effectively degraded cell wall pectin and promoted the release of intracellular active substances, , at the same time, the synergistic enhancement of polyphenol oxidase and peroxidase activities accelerated the decomposition of bound polyphenols, resulting in a significant increase in the free polyphenol content, which in turn enhanced the antioxidant activity of wolfberry fermentation products [61,62]. In addition, LAB contain enzyme systems capable of degrading biogenic amines to the corresponding amino acids [63-66] and increasing vitamin content [66], which increase the safety of LAB fermented products while adding nutritional value. 

LAB can not only effectively hydrolyse macromolecules such as polysaccharides and proteins, but also act on some undesirable substances. Ben Taheur [67] tested four LAB for their ability to inhibit the growth of Aspergillus flavus and Aspergillus carbonarius and the production of mycotoxins. The experimental results showed that LAB were effective in reducing the accumulation of aflatoxins; Ethyl Carbamate (EC) has potential carcinogenic properties and is widely found in most alcoholic beverages. Studies have found that at least five precursor substances exist for EC, including urea, citrulline, and others [68]. During LAB metabolism, it is able to inhibit EC formation through the Arginine Deiminase (ADI) pathway, which results in the catabolism of arginine with the production of citrulline, followed by the action of ornithine transcarbamoylase, which further converts citrulline to ornithine [69,70]. 

LAB fermentation also leads to an increase in volatile substances in the ferment [71,72], which improve the flavor of the fermented product, as well as its antioxidant and bacteriostatic capacity; Moreover, during the fermentation process, LAB will produce a series of metabolites, such as organic acids (mainly including lactic acid, formic acid, acetic acid and propionic acid, etc.) [73], which can enhance the antimicrobial activity of the fermented products; LAB can also produce extracellular polysaccharides [74,75], which have good antioxidant, anticancer and antimicrobial properties. 

At present, most of the mechanistic studies on LAB fermentation are relatively superficial, and the studies can only clarify the enzyme recognition of the substrate and its action results, the molecular mechanism and the action pathway are not thoroughly researched; the interactions of multiple strains of bacteria in the fermentation system are complex, and the key gene functions and regulatory mechanisms are not clear, so in-depth studies are still needed. 

Figure 1: Mechanisms of lactic acid bacteria fermentation; (A) Lactobacillus fermentation promotes leaching of active ingredients; (B) Lactobacillus fermentation is able to act on the biological components of herbs to produce new substances.

• Promoting the Release of Active Ingredients and Enhancing the Pharmacological Activity of CHM 

The effective medicinal components of CHM are very complex, mainly including saponins, organic acids, vitamins, polysaccharides, volatile oils, alkaloids, flavonoids, and so on. Most of these effective components are found in roots, stems, and leaves, surrounded by the plant cell wall, which affects the release of effective components. A variety of enzymes produced by LAB, such as cellulase and pectinase, can break down the tightly structured cell walls and promote the release of active ingredients in CHM [59,61,62,76], thereby contributing to the enhancement of CHM efficacy (Figure 1A). 

For example, by using Lactobacillus plantarum for fermentation of the above-ground parts of Bupleurum officinale, the experimental results showed that the content of rutin isoquercitrin, quercetin-3-O-β-L-arabinoside and DL-3-phenyl-2-hydroxypropionic acid in the fermentation broth for 48 h was significantly increased, and the antimicrobial activity of the fermentation products was also enhanced [77]. Similarly, the fermentation of Codonopsis pilosula with a mixture of three lactic acid bacteria, Bifidobacterium longum (KACC 20587), Lactobacillus enterica (KACC 12312) and Lactobacillus acidophilus (KACC 12419), resulted in a significant increase in the content of trans ferulic, gallic and vanillic acids, and its cognitive and neuroprotective effects were shown to be enhanced by animal experiments [78]. In addition, using Lactobacillus plantarum to ferment Sijunzi Tang and determining the changes in the content of the fermentation broth, the results of the assay showed a marked increase in the amounts of atractylenolides I-III, glycyrrhizin and betacyanin, and the fermentation products had a favorable protective effect on neuronal cells [79]; when ginseng extract was fermented by Lactobacillus plantarum, the contents of rare ginsenosides Rh₁, F₂, Rg₃, and CK in the product were substantially increased, and the ability to scavenge free radicals after fermentation was also improved [80]. 

In conclusion, the enzymes in LAB during CHM fermentation can dissolve cell walls, decompose macromolecules and metabolically modify the products, which can significantly improve the dissolution and activity of the active ingredients.

• Generating New Active Substances 

CHM contain a wide variety of components with complex structures, and LAB can carry out biocatalytic reactions on the characteristic components of CHM through its enzyme system (including proteases, β-glucosidases, lipases, amylases, and other key hydrolytic enzymes). These enzymatic modification reactions not only enhance the bioavailability of the original components, but also generate secondary metabolites with novel pharmacological activities through specific enzymatic reactions such as glycoside hydrolysis and ester bond cleavage, and are capable of expanding indications (Figure 1B). 

For instance, in the case of fermentation of Artemisia annua extract using Lactobacillus plantarum, it was observed that the inhibitory effect on the release of interleukin (IL)-8 was significantly enhanced in the fermented group as compared to the unfermented group, while the fermentation resulted in the production of two new compounds - catechols and decidiol-aspartic acid C [81]; Similarly, fermentation of red ginseng by Lactobacillus plantarum can produce the new active substance ginsenoside Rd [82]; Fermentation of wolfberry juice by Lactobacillus plantarum was able to release bound polyphenols during the fermentation process, resulting in the production of free polyphenols such as scopolamine, dihydroferulic acid, and pyrocatechol in the ferment [61]; In another study, wolfberry juice, after fermentation by Lactobacillus plantarum, showed the appearance of the characteristic secondary metabolite indole-3-lactic acid and the phenol and total flavonoid contents exhibited up-regulated results [83]; There are also many similar studies, such as the analysis of the products of Lactobacillus rhamnosus fermentation of honeysuckle, which showed the appearance of a new substance, 6,7-dihydroxycoumarin, and an increase in the volatile constituents, with the appearance of new compounds, such as citronellol, acrylic acid and fumaric acid, after 96 h of fermentation [84]; After fermentation by Lactobacillus pentosus, Lespedeza cuneata produced kaempferol and quercetin [85]; Lactobacillus buchneri fermented red chilli peppers, and β-carotene was produced in the fermentation product [86]. 

A number of studies have shown that fermentation with LAB produces a series of new active substances, which often have unique chemical structures and biological properties. Therefore, the fermentation of CHM by LAB is an effective strategy for the ‘new use of old drugs’.

• Reducing the Toxicities and Side Effects of CHM 

For thousands of years, the widespread use of CHM has led many people to believe that they are non-toxic and harmless to the human body. However, in recent years, rising incidents of adverse reactions caused by CHM have shattered this perception. The Chinese Pharmacopoeia (2020 Edition) contains 83 toxic CHM. Among them are 10 highly toxic CHMs, including Radix Aconiti, Semen Strychni and Fructus Crotonis [87]. The enzyme system in LAB is capable of degrading or modifying certain toxic components in CHM, thus reducing their toxicity or side effects. 

For example, the neuronal toxicity of Tiger Balm fermentation broth was ameliorated by treatment with LAB fermentation [88]; Similarly, the fermentation of turmeric with LAB resulted in a significant increase in curcumin content, which is not cytotoxic compared to unfermented turmeric, while at the same time significantly reducing the nitrite content, which can greatly enhance its safety [89]; In Furthermore, Lactobacillus plantarum was used to ferment cadmium (Cd)-added soymilk and to assess whether there was a protective effect of fermented soymilk against chronic Cd toxicity in mice. The results showed that fermented soymilk was able to reduce tissue Cd loading and alleviate tissue oxidative stress in mice, as well as improve histopathological changes in mice, which was protective against chronic Cd toxicity [90]. In addition, the fermentation of C. spinosa using Lactobacillus plantarum SY12 not only increased the yield of epigallocatechin gallate, but also attenuated the DNA damage and reduced the toxicity [91]. 

Numerous research results have shown that the safety of CHM can be enhanced after fermentation by LAB. LAB fermentation technology is an effective strategy to reduce the toxic side effects of CHM.

• Protecting the Environment and Reducing Waste of Resources 

In recent years, China's Chinese herbal medicine industry is booming, and its annual output has reached 70 million t. However, in the industrialized processing of pharmaceutical enterprises, after the extraction of the active ingredients of CHM, the dregs and non-medicinal parts of CHM are categorized as wastes, and the solid wastes generated have reached 35 million t, which accounted for 50% of the total medicinal materials, resulting in a large amount of unused and wasted resources, and these wastes contain a lot of reusable components such as proteins, alkaloids, polysaccharides, flavonoids and terpenoids and so on. The ‘Twelfth Five-Year Plan’ proposes the secondary development of traditional valuable Chinese herbal medicines and the reuse of non-traditional medicinal parts of CHM, which is conducive to the sustainable development of CHM resources [92]. How to reasonably dispose of and resourcefully utilize the waste of CHM has become a crucial issue that needs to be solved for the development of the current industry. 

It was found that fermentation of the herbal residue of gastrointestinal tablets using Lactobacillus plantarum was able to inhibit the infectious activity of Helicobacter pylori [93]; In addition, in another study on the dregs of gastrointestinal tablets, it has been found that the involvement of Lactobacillus plantarum in the fermentation of dregs can significantly improve the immunity of mice [94]; In addition, the monosodium glutamate in date residue can be converted into γ-aminobutyric acid by Lactobacillus shortus fermentation. It is well known that γ-aminobutyric acid, as an inhibitory transmitter in the central nervous system, is able to reduce neuronal excitability. Therefore, fermentation of date residue has the potential to be used as a fatigue-relieving, sedative-hypnotic drug [95]; LAB was used for solid fermentation of Rabdosia rubescens dregs, and the content of oleanolic acid, ursolic acid and other active ingredients in the dregs increased after fermentation [96]; Meanwhile, some researchers used LAB to ferment Astragalus dregs in solid state, and the results showed that the content of single-cell proteins in the fermented product increased significantly . Based on this result, Astragalus dregs can be recycled for feed industry [97]; Using LAB to ferment agro-industrial wastes and feeding guinea pigs with the fermented substrate. The experimental data showed that there was no mortality and the incidence of diarrhoea decreased in guinea pigs in the Lactobacillus acidophilus and Lactobacillus bulgaricus groups [98]. Besides, Green tea residues fermented by Lactobacillus plantarum can produce bioactive peptides [99]. Bioactive peptides have antioxidant, immune-regulating, and blood pressure and lipid-lowering effects, so the use of LAB fermentation can help transform agricultural waste into renewable resources; furthermore, LAB grows well on substrates with food waste and other biowastes as the main ingredient [100], therefore, LAB fermentation can be used as an environmentally friendly waste treatment technology. 

The use of LAB fermentation can make full use of a wide range of raw materials that would have been wasted and transform them into valuable products. This process not only reduces resource wastage, but also contributes to sustainable development goals.

• Solid fermentation 

Solid fermentation has a long history of development from the traditional brewing process. Solid fermentation is the process of mixing CHM and strains of bacteria in a certain proportion and then inoculating them into solid substrates such as grains or agricultural products for fermentation and cultivation. In this fermentation system, the moisture content is extremely low, it is naturally open, and there is no need for sterilization [101] (Figure 2). 

For example, a variety of grains were solidly fermented using LAB. The results showed an increase in the content of γ-aminobutyric acid from 4.64 mg/g to 6.93 mg/g in the fermented compared to the unfermented grains, as well as an increase in free radical scavenging activity [102]. Similarly, the use of LAB involved in solid fermentation of soybeans not only produced soybean polypeptides, but also reduced the content of trypsin inhibitors and antibody proteins, with which the antioxidant activity of the fermentation products was significantly increased [103]. In addition, after fermentation of ginseng seeds using Lactobacillus fermentum, the products showed increased levels of total sugars, phenolic compounds and acidic polysaccharides after fermentation compared to unfermented controls [104]. Solid-state fermentation of Astragalus membranaceus with Lactobacillus plantarum increased the content of polysaccharides, total saponins and flavonoids [105]. Whereas, fermentation of Sophora japonica using LAB increased the total flavonoid content and genistein by 2.90 times compared to the original herb [106]. 

Solid fermentation is a simple method of operation with good fermentation results and low risk of contamination, but there are disadvantages such as long fermentation cycles and difficulty in controlling specific fermentation stages.

Liquid fermentation is developed from antibiotic production [107], which uses CHM solution and liquid medium as the nutrient substrate. During fermentation parameters such as temperature, pH and dissolved oxygen need to be considered [101] (Figure 2). 

For example, by using Lactobacillus fermentum for the fermentation of Ssanghwa-tang, a commonly used Korean remedy, it was found that the amount of Liquiritigenin, cinnamaldehyde, Decursin, Decursinol angelate and other components in the fermented product was reduced, and a new component, Liquiritigenin, was found, as well as an increase in the amount of cinnamaldehyde, Decursinol and other components [108]; The fermentation of LAB is able to convert the polysaccharides in Polygonatum sibiricum into monosaccharides and improve the antioxidant capacity of the product, while the vigour of enzymes such as protease and amylase is increased, and the taste is also improved [109,110]; Some researchers found that by liquid fermentation of Coix lacryma, with only 1% inoculation of Lactobacillus plantarum, the total phenol content of the product could reach 169.10 mg/mL, and the content of β-glucan could achieve 0.56 g/mL, which greatly improved the nutritional value of Coix lacryma [111]. The use of Lactobacillus plantarum and Lactobacillus paracasei for the fermentation of compound CHM yielded a polysaccharide content 2.51 times higher than that of the unfermented product [112]. Using Lactobacillus paracasei and Bifidobacterium longum to transform ginsenosides contained in red ginseng, the fermentation obtained was protective against ovalbumin-induced inflammation in mice [113]; similarly, using Lactococcus lactis for fermentation of hydroponically grown ginseng resulted in a significant increase in the phenolic and flavonoid content of the product and exhibited substantially enhanced antioxidant activity [114].

The advantages of liquid fermentation are short cycle time, high efficiency and suitability for large-scale production, but the cost of equipment is higher and the risk of contamination is greater.

 Figure 2: The way lactic acid bacteria ferment herbs.

• Antitumour 

Current therapies for tumor-based diseases are mostly non-cancer-specific means of chemotherapy and radiotherapy, which may cause damage to normal cells as well. Bacteriocins have been found to impede the growth of a wide range of cancer cell lines and to exhibit low toxicity to normal cells because they target microorganisms of the same or similar species [115,116]. The main anti-cancer mechanisms identified for bacteriocins include disruption of the cell cycle, induction of cell death, disruption of cell membrane structure, restriction of cell migration, effects on the immune system and inhibition of angiogenesis and so on [117-121]. Bacteriocin is a peptide produced by bacteria, mainly from LAB and it is biodegradable [122]. The membrane-active peptides (cationic peptides) produced by bacteriocins would contact and interact with negatively charged cell walls. Whereas cancer cells have a higher concentration of negative charges on their surface and a thinner cell membrane, which bacteriocins are able to attack and cause their cell membranes to cleave [123]. Bacteriocins can also act on lipid II in the cell wall. It can bind to lipid II to interfere with the transport of peptidoglycan subunits from the cytoplasm to the cell wall, inhibiting cell wall formation or using lipid II as a docking molecule to form pores in the membrane leading to the rapid death of cancer cells [124]. 

For example, astragalus polysaccharides may play an adjuvant role in anti-tumor therapy. Using FGM LAB strain to ferment Astragalus, and conduct animal experiments. It was found that the levels of interleukin 1β and tumor necrosis factor-α (TNF-α) in mice decreased significantly after astragalus polysaccharides were obtained in the product, and the astragalus fermentation was able to reduce inflammation and improve immunity [125].

In conclusion, LAB-fermented CHM can complement chemotherapy in antitumor therapy. It can reduce adverse effects, enhance therapeutic efficacy and improve patients' immunity.

• Antioxidant 

The human body produces free radicals during metabolism, which attack cells and trigger a series of negative consequences. Some antioxidant enzymes produced by LAB, such as catalase and superoxide dismutase, are able to scavenge free radicals, and the antioxidant activity of the fermentation broth is enhanced when certain CHM are fermented with LAB. For example, all of the antioxidant capacity of goldenseal was enhanced after fermentation of goldenseal by Lactobacillus longum [6]; Schisandra chinensis dregs showed increased dissolution of antioxidant active ingredients after fermentation with Lactobacillus paracasei, and the fermented dregs were verified by animal experiments to have a mitigating effect on a mouse model of oxidative damage from fermentation [126]; After fermentation of red kale shoots with three types of LAB, it was able to observe a significant increase in antioxidant activity and a decrease in the total phenol content of the fermentate after 24 h of fermentation with all three types of LAB [127]; Similarly, chamomile flowers fermented by Lactobacillus plantarum increased the free radical trapping capacity of the product by 11.1% [128], and Lactobacillus fermentation of avocado leaves significantly increased the antioxidant capacity of the product and increased the bioavailability of the active substance [129]; furthermore, analysis of the LAB fermentation broth of mulberry was able to reveal an elevated free radical scavenging rate [130]. 

These and several other studies have shown that most CHM have improved free radical scavenging ability after fermentation with LAB. Free radicals cause a variety of cellular damage: damaged vascular endothelial cells lead to an increased risk of cardiovascular disease, damaged neurons advance the course of neurodegenerative diseases, and in the case of diabetes, the body of patients with hyperglycaemia produces large quantities of free radicals [131]. As a result, the use of LAB to ferment CHM can play a catalytic role in scavenging free radicals and provide ameliorative ideas for a wide range of diseases.

• Hypoglycaemia 

Abnormally high blood glucose levels can cause diabetes, and prolonged high blood glucose levels can lead to a range of complications. Diabetes is a disease with a very high prevalence worldwide [132,133]. It was found that fermentation of carrots using Lactobacillus plantarum resulted in a decrease in the content of water-soluble polysaccharides in the product, which was validated using a diabetic rat model, demonstrating its effectiveness in intervening in type II diabetes mellitus [134]. Similarly, Lactobacillus plantarum was used to ferment red ginseng and experiments were carried out on the fermentation products using a streptozotocin-induced diabetic mouse model. The results showed a significant reduction in fasting blood glucose levels in the fermented group, as well as a significant increase in glucose tolerance in this group, greatly improving the diabetic condition of the mice [135]. Similarly, fermentation of buckwheat using Lactobacillus plantarum and Lactobacillus paracasei, respectively, showed the highest α-glucosidase inhibitory activity in the Lactobacillus plantarum group, and the highest inhibition of dipeptidyl peptidase IV in the Lactobacillus paracasei group. This result shows the potential of buckwheat fermentation products for glycaemic regulation in diabetic diet [136].

• Other Application Areas of Lab 

There are other active improvements in the fermentation of CHM by LAB. For example, after fermentation by LAB, the Radix Scrophulariae exhibits anti-inflammatory activity [137]; Similarly, LAB-fermented cactus polysaccharides have a reparative effect on inflammatory damage in human keratin-forming cells [138]; In addition, a study using a mixture of three LABs to ferment mulberry leaf extract showed that the fermented mulberry leaf extract prevented constipation [139]; Another study found that the product of LAB fermentation of ginseng could reverse spatial memory deficits in rats and had the effect of preventing apoptotic death of hippocampal neurons [140]; Using high-fat diet-induced obese rats as the target, to study the therapeutic effect of fermented pomelo pomace by LAB on them. It was found that the epithelial fat cells were significantly smaller and the number of lipid droplets in hepatocytes was lower in the fermentation group, which proved the effectiveness of pomelo pomace fermentation in the treatment of obesity [141]; Fermentation of red seaweed with LAB resulted in a significant increase in the inhibition of oral pathogens while reducing polyphenolic content [142]. 

In summary, the products obtained from fermentation of CHM by LAB show potential therapeutic and preventive effects in a wide range of diseases, such as antibacterial and anti-inflammatory, immune regulation, antioxidant, etc., by virtue of their unique bioactive compositions and effects, which provide new ideas and directions for the research and development of new medicines, the development of functional foods, and the optimization of clinical therapeutic protocols.

CHM contain a large number of active substances with a wide range of pharmacological activities. Fermentation by LAB can promote the release of active substances in CHM or reduce the toxicity of certain components, therefore, the development of a new strategy for the fermentation of CHM by LAB is of great value. At present, it is found that for the fermentation process, the interaction relationship between different LAB and CHM components has not been completely clarified, the specific molecular mechanism is still unknown, most of the studies focus on the fermentation of simple sugars by LAB, in addition, in the actual production and application, the quality control and stability of the fermentation product is still a major challenge. 

In order to achieve high yield, stability and productivity of LAB fermentation products, many researchers have carried out active and in-depth improvement exploration and research work from multiple dimensions. An example is the use of synthetic biology in LAB fermentation [143]. High-throughput sequencing technology and bioinformatics analysis can accurately resolve the metabolic network and gene expression during LAB fermentation [144], while gene editing technology can achieve targeted modification of LAB. For example, using genome engineering to improve LAB [145], the minimum inhibitory concentration of Lcn972 bacteriocin was significantly increased and anti-microbial resistance was improved [146]. Furthermore, when LAB are applied in large-scale production, they are often subject to growth inhibition caused by the end product lactic acid, However, the mutation of LAB resulted in an increase in acid tolerance, which favored an increase in d-lactic acid [147]. 

Therefore, the rapid development of multi-omics technologies (genomics, transcriptomics, proteomics and metabolomics) can reveal the regulation of key gene expression in LAB during fermentation at the genetic level. The transcriptome analyses the dynamics of mRNA expression, the proteome probes the changes in protein synthesis and modification, and the metabolome detects the changes in metabolites, which comprehensively and deeply elaborates the molecular mechanism of LAB fermentation and provides a multi-dimensional theoretical basis for the optimization of fermentation process [148]. With the development and application of high-tech experimental research technology, the fermentation mechanism of LAB fermentation of CHM will be clearer, the application scope will be broader, and the research in the fields of gastrointestinal diseases, cardiovascular diseases, and neurological disorders will make greater breakthroughs.

The study did not receive any specific funding from funding organizations in the public, commercial or non-profit sectors.

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