Chemical components of Fu brick tea and its potential preventive effects on metabolic syndrome

Abstract As living standards advance, an escalating emphasis is placed on health, particularly in relation to prevalent chronic metabolic disorders. It is necessary to explore safe and effective functional foods or drugs. Fu brick tea (FBT) is a kind of dark tea fermented by fungi. The extracts are rich in compounds that can effectively relieve metabolic diseases such as hyperglycemia and hyperlipidemia, protect the liver, improve human immunity, enhance antioxidant activity, and regulate intestinal flora. This paper summarizes the biological activities and mechanisms of the extracts, polysaccharides, and small molecular compounds of FBT, which provides a certain theoretical basis for the rational, systematic, comprehensive development and utilization of the FBT resources. It is expected to develop and apply these active substances in health care products and natural medicines and provide more beneficial and diversified FBT products for human beings.

Due to the diverse biochemical components and health-beneficial functions of FBT, the research on FBT has attracted much attention.And many excellent reviews on this subject have been published so far.In 2021, Lin et al. reviewed the microbial fermentation of dark tea, main bioactive compounds, and important biological functions, emphasizing their protective effects against various diseases and relevant molecular mechanisms (Lin et al., 2021).In 2021, Shang et al. reviewed the compounds and health mechanisms of dark teas (Shang et al., 2021).In 2021, Chen et al. reviewed the fermentation processing, microorganisms, chemical constituents, health benefits, and potential risk of FBT (Chen, Bai, et al., 2021).Compared with these reviews, our article focused on FBT, one kind of dark tea, and its diverse compounds.This article reviews some common diseases related to metabolic syndrome (MetS) in recent years (Table 1), including inflammatory bowel disease (IBD), intestinal flora disorder, obesity, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), diabetes, etc.The urgency of prevention and treatment of these common diseases, the drugs used in clinic, and the existing problems are summarized.These diseases exhibit a high prevalence while suffering from a low therapeutic efficacy.The drugs currently used in clinical have certain limiting effects, but FBT shows potential therapeutic effects on these diseases and has the possibility of developing into prebiotics or drugs (Hu et al., 2018).
In view of the potential activity of FBT on a variety of common diseases, the different chemical components produced by FBT are summarized, including polysaccharides, small molecular compounds, and water/organic solvent extracts (Chen, Chen, et al., 2022).The biological functions and mechanisms of various chemical components are also concluded.This review aims to explore potential safe drugs for relieving and treating obesity, hyperlipidemia, diabetes, and colitis.At the same time, it would be helpful to develop functional food or food additives of FBT to improve human health and prevent diseases.

| B I OLOG I C AL AC TIVIT Y OF FBT P OLYSACCHARIDE
In recent years, polysaccharides, as therapeutic agents and mediators of complex cell systems, have become important due to their multiple biological functions.In addition, polysaccharides have little toxic and side effects and have great potential to be developed into medicine or functional food (Chen, Wang, et al., 2022;Chen, Xie, Dai, et al., 2018;Shashidhar et al., 2015).Many studies have shown that complex carbohydrates, which are difficult to digest in the host, are fermented by the flora in the cecum and colon.These carbohydrates regulate intestinal flora by regulating the intestinal flora (Chen, Chen, et al., 2022).Therefore, the digestive process of complex polysaccharides in the intestine is of great significance for regulating immune responses and balancing intestinal flora.FBT polysaccharide is such a typical acid heteropolysaccharide that is difficult to digest (Chen, Li, et al., 2021;Chen, Wang, et al., 2022;Yang et al., 2021).They can directly pass through the upper digestive system and use intestinal flora to reach the large intestine.FBT polysaccharide is the main effective bioactive ingredient, which has biological functions such as weight loss, antioxidation, and immunity enhancement.Therefore, it has been paid more and more attention by people in recent years (Li et al., 2018;Liu, Wang, et al., 2022).

| Regulation of FBT polysaccharide on metabolism
FBT polysaccharide can reduce colon tissue damage and inflammation.Researchers found that FBT polysaccharide could reduce ulcerative colitis, reduce the disease activity index of mice, prevent colon shortening, and improve colitis (Chen, Xie, Wan, et al., 2018;Lu et al., 2022;Yang et al., 2021).FBT polysaccharide can regulate the composition of intestinal flora; on the other hand, it can promote the production of shortchain fatty acids as metabolites of intestinal flora, thus improving the intestinal environment.For example, for ulcerative colitis induced by sodium dextran sulfate, FBT polysaccharide can effectively alleviate the intestinal flora disorder caused by colitis, promote the increase of beneficial bacteria such as lactic acid bacteria and Ackermann bacteria, and thus significantly increase the level of short-chain fatty acids.In addition, it can also improve the tryptophan metabolism of intestinal microorganisms in patients with ulcerative colitis and increase the content of indole-3-acetic acid and indole-3-acetaldehyde in feces (Yang et al., 2021;Zhang, Ren, Zhao, Shao, et al., 2022).

| Regulation of FBT polysaccharide on IBD
Polysaccharides can assist in the treatment of IBD (Berg et al., 2013;Chen et al., 2023;Thomas & Morgan, 2013).The anti-inflammatory activity of natural polysaccharides has gradually become a new way to relieve or treat intestinal inflammation (Xie et al., 2020) FBT polysaccharide can improve IBD by regulating intestinal flora and promoting their metabolism.Some researchers studied the relationship between the anti-inflammatory effect of the purified FBT polysaccharide and intestinal flora (Chen, Chen, et al., 2022;Kang et al., 2019).The intestinal flora of subjects with IBD can utilize and degrade the FBT polysaccharide.At the same time, FBT polysaccharide can regulate the structure of intestinal flora in patients with IBD, making it close to the healthy group.For example, increase the bacteroides spp.and reduce the Escherichia/Shigella (Yang et al., 2021).In addition, the content of short-chain fatty acids increased significantly.Thus, FBT polysaccharide is expected to be a new probiotic to treat IBD by regulating intestinal flora and promoting the production of short-chain fatty acids.
FBT polysaccharide can improve IBD by repairing the intestinal barrier.Zeng and Bai et al. studied the anti-inflammatory activity of crude and purified FBT polysaccharide on mice with colitis induced by sodium dextran (Bai et al., 2022;Zeng et al., 2022).It was found that the expression of lipocalcemin-2 was significantly reduced in colitis.Both crude and refined FBT polysaccharides could recover the intestinal injury induced by cyclophosphamide.It can restore the intestinal morphology and the expression of tight junction proteins (Occludin, Claudin-1, and ZO-1).

| Immunomodulatory effect of FBT polysaccharides
The immune system is a reliable defense for protecting human health (Chen et al., 2019;Ding et al., 2019).Some polysaccharides can activate host immune cells and further promote the secretion of a variety of inflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor TNF-α, thus exhibiting significant immunomodulatory and anti-tumor effects (Chen et al., 2023).
Improving immune function is one of the most important biological activities of the FBT polysaccharide.Recently, researchers extracted and purified FBT polysaccharide, which can increase the phagocytosis ability of macrophages RAW264.7,stimulate the secretion of nitric oxide and other inflammatory cytokines (TNF-α, IL-1β, IL-6).It also has obvious immune enhancement activity in vitro.
Therefore, FBT polysaccharide can be used as a potential functional food to protect human health by regulating the immune response of the host (Chen, Bai, et al., 2021).
In addition to regulating the immune response by directly acting on immune cells and inflammatory cytokines, FBT polysaccharide can also regulate the immune process by acting on host intestinal microorganisms and secondary metabolites produced by microorganisms (Klausz et al., 2015;Li et al., 2016).FBT polysaccharide has immune protection effect on immunosuppressed mice induced by cyclophosphamide (Bai et al., 2022).It can obviously restore the microbial imbalance caused by cyclophosphamide, increase the abundance of some beneficial bacteria, and reduce the abundance of Spirobacteriaceae, Clostridaceae, and other strains.The metabonomic analysis showed that FBT polysaccharide significantly changed a series of microbial metabolites, including erucic acid, butyric acid, lysophosphatidic acid, deoxyinosine, taurine, maltotriose, lysophosphatidylcholine, choline, and inosine.These altered metabolites participate in sulfur metabolism, purine metabolism, interaction of neuroactive ligand receptors, phenylpropanoid biosynthesis, protein digestion and absorption, tumor choline metabolism, and glycerol phospholipid metabolism pathways, which are mainly related to antioxidant capacity, immune response, and energy supply of immunosuppressed mice.In addition, there is a significant correlation between specific flora and effective metabolites (Bai et al., 2022).Therefore, FBT polysaccharide can protect the host by regulating intestinal flora and metabolism.
The structural characteristics and immunomodulatory properties of the FBT polysaccharides vary with different extraction methods.Compared with the water extraction of the FBT polysaccharide, the polysaccharide extracted from alkali has a high yield, and the composition of monosaccharide has also changed (Sun et al., 2022).
In vitro studies, the FBT polysaccharide extracted from alkali has a significant impact on the acid phosphatase activity, phagocytosis, showing a good role in regulating immune imbalance.

| Antioxidant activity of FBT polysaccharide
The antioxidant activities of FBT polysaccharide include: the scavenging activity of 1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical (range: 54.3 ± 1.9~67.8± 2.5%), the obvious scavenging activity of superoxide free radical (more than 85%), and the better scavenging activity of ABTS free radical (nearly 100%).In addition, FBT polysaccharide has a protective effect on the oxidative damage of rat pheochromocytoma cells induced by hydrogen peroxide (Chen, Wang, Xie, et al., 2018); FBT polysaccharide can significantly improve the oxidative damage in mice.Therefore, FBT polysaccharide, as a natural and safe antioxidant, has potential application prospects in functional foods.

MIC values against enteropathogenic Streptococcus typhi and
Escherichia coli were 800 and 400 μg/mL, respectively.The inhibitory activity against dysentery bacillus was equivalent to that of berberine hydrochloride, with a MIC value of 100 μg/mL (Keller & Wallace, 2021;Kondo et al., 2018;Ling et al., 2010).The compounds may be a potentially safe anti-dysentery drug or lead compound.
To sum up, abundant small-molecule compounds were isolated from FBT.Some of the compounds showed biological activity, had antibacterial activity against some intestinal pathogenic microorganisms.The results of the current study show that the role of small molecular compounds in regulating metabolic diseases is weak.

| B I OLOG I C AL AC TIVIT Y OF FBT E X TR AC TS
Nowadays, FBT has become an indispensable drink in northwest China, and there is a saying that "it is better to be without food for three days than without tea for one day" (Emami Arjomand et al., 2021;Hayat et al., 2015;Xu et al., 2022;Zheng et al., 2022).In order to further analyze its functional components, the researchers obtained the organic solvent and water extracts of FBT and found that the extracts had various components, including polyphenols, amino acids, organic acids, polysaccharides, and pigments.In addition to forming the unique flavor and aroma of FBT, it also made FBT have a variety of significant biological activities, such as weight loss, blood lipid reduction, anti-oxidation, and antibacterial (Li, Lo, et al., 2013;Liu et al., 2015).

| Regulatory effect of FBT extracts on obesity and hyperlipidemia
In the past decades, obesity has become an urgent global public health problem, contributing to heart disease, hyperlipidemia, hypertension, diabetes, and fatty liver (Zhou et al., 2022;Zhou, Li, et al., 2021).FBT extracts have the potential function of preventing obesity.For example, the water extracts of FBT can significantly inhibit the fat deposition of adipocytes in Caenorhabditis elegans (Peng et al., 2014).In addition, the water extracts of FBT can also significantly inhibit the weight increase and adipose tissue accumulation of obese rats induced by a high-fat diet.And the water extracts could also reduce the levels of total cholesterol, serum triacylglycerol, and low-density lipoprotein.Thus, FBT extracts have significant effects on weight loss and blood lipid reduction (Li, Liu, et al., 2013;Zeng et al., 2022;Zhou, Tian, et al., 2021).
The mechanism of weight loss and blood lipid reduction of FBT extracts is the result of the joint action of different genes (Goldschmidt et al., 2011;Li et al., 2019;Liu et al., 2019;Wilfley et al., 2017): the energy consumption and lipid conversion can be increased by improving the expression of fatty acid oxidation-related genes, such as liver peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1α; lipid storage in tissues can be reduced by enhancing the expression of cholesterol clearance-related genes in the blood, such as low-density lipoprotein receptor; fat synthesis can been reduced by inhibiting the expression of lipid metabolism-related genes, such as fatty acid synthase, sterol regulatory element binding protein-1C, and CCAAT/enhancer binding protein α (Li, Lo, et al., 2013).

| Regulatory effect of FBT extracts on NAFLD
In recent years, FBT has shown a curative effect on NAFLD and related MetS.The water extracts of FBT can reduce the effect of high-fat diet on the rat liver and kidney (Du et al., 2019;Li, Liu, et al., 2013).Fat production of rats fed with FBT extracts was re-

| Protective effect of FBT extracts on liver
The water extracts of FBT can reduce the liver dysfunction and intestinal flora imbalance of the high-fructose fed mice (Wang et al., 2015;Zhang et al., 2019).It has a strong inhibitory effect on dyslipidemia, liver weight increase, serum enzyme activity, and the formation of liver inflammatory cytokines in mice fed with high fructose.The treatment of water extracts of FBT reduced the formation of malondialdehyde in the liver and increased the activities of glutathione peroxidase and superoxide dismutase.At the same time, the abundance of Bacteroidetes in the intestinal tract of high-fructose fed mice was significantly increased, and the number of Firmicutes, Proteobacteria was decreased (Chen, Xie, Dai, et al., 2018;Zhang et al., 2019).These results indicate that the water extracts of FBT can protect the liver by improving oxidative stress, inflammatory reaction, and intestinal flora dysfunction (Chai & Jung, 2022).

| Antioxidant activity of FBT extracts
FBT extracts contain a large number of polysaccharides, polyphenols, and flavonoids, which have good antioxidant activity (Song & Gao, 2014;Zhang et al., 2017;Zhao et al., 2022) have a protective effect on the oxidative stress of human intestinal epithelial adenocarcinoma cell Caco-2 induced by hydrogen peroxide.The methanol extracts can inhibit lipid peroxidation, increase glutathione levels, and antioxidant enzyme activity (Song & Gao, 2014).The n-hexane extracts of FBT mainly include gallic acid, theaflavin, theobromine, caffeine, epicatechin, and quercetin.They show antiaging effect in cell melanin A and mice and can significantly reduce the production of reactive oxygen species in melanin A cell (Zhao et al., 2022).
Apart from methanol and n-hexane organic solvent extracts, the water extracts of FBT also show strong antioxidant activity (Xu, Sun, et al., 2019;Zhao et al., 2018).

| CON CLUS ION
FBT is a unique post-fermentation tea product.Fungal fermentation has a significant impact on the biochemical characteristics of FBT (Li et al., 2017;Xia et al., 2022;Xu et al., 2015Xu et al., , 2020)).After fermentation, various metabolic products, including polysaccharides and polyphenols, provide a variety of options for the development of functional products of FBT (Darwish & Xie, 2012;Dridi et al., 2010;Patil et al., 2015;Powell-Cope et al., 2014;Wang, Zhao, et al., 2021).FBT polysaccharide has high antioxidant activity in vitro and maintains human health by regulating metabolic processes and immune activity.In addition, FBT polysaccharide has a regulatory effect on IBD.Therefore, FBT polysaccharide is expected to be a natural antioxidant, providing potential safe drugs But there is no direct evidence to confirm that.
To sum up, in terms of function, FBT shows rich biological activities (Leonardo et al., 2020;Roth et al., 2022;Sasa et al., 2022;Schur et al., 2020), such as antioxidation, anti-inflammatory, antimetabolic syndrome, antitumor, regulation of glucose metabolism, regulation of intestinal microorganisms, and improvement of immune activity.However, there are few reports on the isolation and identification of small molecular compounds that can alleviate and treat metabolic diseases.The functional evaluation has been carried out on the small molecular compounds.It can provide a strong guarantee and technical support for the further processing and quality control of FBT products.And there is a need for clinical studies on this subject.
flora are involved in the pathophysiological process of MetS.FBT polysaccharide treatment increased the phylogenetic diversity of intestinal flora in mice induced by a highfat diet, and the relative abundance of the Corynebacterium family and Streptococcus family increased.Therefore, the inhibitory effect of FBT polysaccharide on the MetS of mice induced by a high-fat diet is related to the regulation of intestinal flora.FBT polysaccharide can be used as a candidate drug to prevent MetS related to intestinal flora regulation.
and nitric oxide secretion of macrophages.In vivo studies, compared with water-extracted FBT polysaccharide, high doses of alkali extractions showed a considerable or even stronger immune protection and antioxidant activity in the immunosuppressed mice induced by cytoxan.Alkali extracts of FBT polysaccharide can improve intestinal flora composition and intestinal mucosal barrier function,

4
Compounds isolated from FBT byTian and Lu et al.    , glycosides and their metabolites were involved in regulating hypoglycemia and lowering blood lipids.In addition, fuzhuanin B (39) and camellikaempferoside A (61) had antiproliferationactivity. 3β,6α,13β-trihydroxyolean-7-one (36) duced.Meanwhile, β-oxidation tricarboxylic acid circulation, and respiratory chain increased, which mainly contributed to improving NAFLD-related liver fat accumulation.A large amount of protein is involved in the metabolism of sugar and lipids, such as fatty acid synthase and other proteins mentioned above.Further research shows that the water extracts of FBT have free radical scavenging activity, good glycosidase inhibition, alleviation of insulin resistance, and hypoglycemic activity in HepG2 cells in type 2 diabetes mice and can activate the receptor cascade signal pathway activated by phosphatidylinositol 3-kinase-Akt-peroxisome proliferation.Regulate glycolipid metabolism and change the activities of key enzymes related to glycolipid metabolism(Zhu et al., 2021).
for the relief and treatment of colitis.At present, a variety of smallmolecule compounds have been isolated from FBT.Some of them have diverse activities, such as antiproliferation activity, antibacterial activity, blood lipid lowering, and blood glucose lowering effects on Hela and other cells.These compounds mainly included 1 isoprene-reducing compound, 6 flavan-3-alcohols, fuzhuanins A-F, 7 acylated flavonoid glycosides, and 3 triterpenoids.There are still many unknown compounds that need to be further isolated, purified, and identified.Their beneficial effects on health and underlying mechanisms need to be studied.The water/methanol/n-hexane extracts of FBT have antioxidant activity.These extracts can significantly regulate obesity, hyperlipidemia, and NAFLD and have a protective effect on the liver.Therefore, FBT extracts have the possibility of developing into prebiotics or drugs.The molecular function mechanisms of FBT are diverse, with MAPK and TNF signaling pathways being the key ones.Some studies have shown that FBT prevents obesity and hyperlipidemia by regulating gut flora.

. FBT | 37 LI et al. TA B L E 1 FBT shows potential therapeutic effect on some common symptoms. Symptoms Urgency of prevention and control Current drugs for clinical use Problems in clinical drugs Therapeutic potential of FBT References
polysaccharide can alleviate IBD by regulating intestinal flora disorders, promoting microbial metabolism, and repairing the intestinal barrier.