1. Introduction

Studies on the relationship between gut microbiota and health have garnered much interest in recent years. The term “gut microbiota” is defined as the microbial ecosystem or community that resides within the human intestinal tract [1]. The gut ecosystem comprises microorganisms, mainly bacteria, and a small number of viruses, protozoa, and eukaryotic organisms such as fungi that are distributed throughout the gastrointestinal tract [2]. As stated by Nahoum et al., 2016, diversified microbiota are a crucial indicator of good health and well-being [3].

Gut microbiota play an important role in human health, and they are considered a “forgotten organ” and “super-organism” that maintains intestinal epithelium integrity ^[4][5][6][4,5,6]. The human gut contains an estimated 100 trillion microorganisms [7]; in addition, over 1000 different species of microbes colonize the human gut [8]. The dominant groups of bacteria phyla in the gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria ^[5][9][5,9]. Fusobacteria, Cyanobacteria, and Verrucomicrobia phyla are usually less well-represented [10].

Gut microbiota may also play a role in how drugs are metabolized in our body [11]. These commensal bacteria play important roles as key regulators of digestion, involving the extraction, synthesis, and absorption of many nutrients and metabolites, including bile acids, lipids, amino acids, vitamins, and short-chain fatty acids (SCFAs) [11]. The gut microbiota also have a crucial immune function against pathogenic bacteria colonization through many competition processes [12]. They inhibit pathogenic bacteria growth by consuming available nutrients, by pH modification, and by producing bacteriocins, which are a type of antimicrobial peptide secretion, affecting cell signaling pathways [13].

Gut microbiota imbalance (dysbiosis) is associated with the development of a series of diseases ^{[14][15][16][17][18][19]}[14,15,16,17,18,19]. These diseases include diabetes, obesity, cardiovascular and liver diseases, cancers, multiple sclerosis, and neurodegenerative diseases ^{[14][15][16][17][18][19]}[14,15,16,17,18,19]. Hence, the gut microbiota has been proposed as a promising therapeutic target for these diseases [20].

Research is still ongoing into the factors that modulate gut microbiota profiles, and diet could play a role ^[21][22][23][21,22,23]. However, studies suggest that diet only accounts for a low percentage of microbiome variation after adjusting for other contributing co-variates, such as genetics, age, ethnicity, geographic origins, body mass index (BMI), lifestyle, medication, and environmental factors ^[12][24][12,24].

Dietary intake varies from one individual to another, and there is a complex interaction between dietary intake and the gut microbiome [25]. The so-called “Western diet” is characterized as high-calorie and is associated with metabolic syndrome i.e., abnormal lipid profiles, elevated blood pressure, and impaired fasting glucose [2]. Evidence suggests that the so-called “Mediterranean diet,” which is high in the polyunsaturated fatty acids and polyphenols (from coffee, tea, or grapes), is associated with an increased gut microbiota diversity [26].

Tea (Camellia sinensis sp.) is one of the most widely consumed nonalcoholic beverages in the world [27]. There are different types of tea: green tea, oolong tea, black tea, Pu-erh tea, and dark tea. Each tea is produced differently using different fermentation processes. Tea is rich in polyphenols, possesses antioxidant properties, and offers multiple health benefits [28]. Flavonoids such as flavanols (catechins, gallocatechins, and epicatechins), flavonols (kaempferol and quercetin), and phenolic acids are the three major classes of polyphenols in tea [29].

Polyphenols are absorbed in the small intestine and may reach the colon [30]. These polyphenols may modulate the gut microbiota composition, and the gut microbiota may catabolize polyphenols into metabolites such as phenolic acids [31]. The metabolites are absorbed more efficiently compared with the parent polyphenols compounds. These metabolites might be further conjugated as O-methylated, sulphated, and glucuronidated in the liver before being excreted [32]. In vitro studies have shown that the polyphenols in tea are biotransformed to active metabolites by the gut microbiota through enzymatic activities and the increased bioavailability of polyphenols ^[33][34][33,34]. Polyphenols such as flavanols, including catechins, modulate the composition of the gut microbial community, mostly through the inhibition of pathogenic bacteria and the stimulation of beneficial bacteria species such as Bacteroides galacturonicus, Lactobacillus sp., Enterococcus caccae, Bifidobacterium catenulatum, Ruminococcus gauvreauii, and Escherichia coli ^[34][35][34,35]. Previous studies have shown that the synergistic effect of tea polyphenols and gut microbiota has subsequently influenced the host biochemical processes, establishing a system of mutual interaction and inter-dependency [36]. The presence of polyphenols could increase the host immune system and metabolic responses through the modulation of gut microbiota [36].

Evidence suggests that polyphenols may also modulate the gut microbiota in what is known as a prebiotic-like effect [20]. However, Ivey et al., 2019 reported that dietary flavanols produce a vast potential complexity of interactions when combined with the phylogenetic and functional diversity of the human gut microbiota [37]. This complexity is linked to the capacity of flavanols to promote beneficial bacteria or suppress pathogenic bacteria ^[38][39][40][38,39,40].

To the best of our knowledge, the effects of tea on gut microbiota were studied in cells (in vitro) and in mechanistic studies on animal models (in vivo) ^{[41][42][43][44]}[41,42,43,44]. However, studies using cell lines or animal models to study gut microbiota have their own limitations. Casotta et al., 2020 showed that findings from animal models and cell cultures do not represent and are not translatable to humans [45]. The main limitation of in vivo studies is due to the host’s tolerance of microbial infections, which varies greatly across different species [46]. In vitro colonic fermentation models are cheaper, are more reproducible, and can be conducted in a shorter time compared with in vivo studies [47]. Pham et al., 2018 showed several limitations of cell studies, including the absence of human or animal cells and low pH, which reduces microbial activity [47].

Furthermore, it remains a challenge to translate findings obtained from cells and animal models to humans [48].