The gut microbiome, comprising the genetic material of microorganisms like fungi, protozoa, bacteria, etc, resides in the digestive tracts of humans and other animals ( Table 1 ), including insects (Liang et al., 2018). Having evolved alongside its host for millennia, the human gut microbiome plays a crucial role in various essential activities, including nutrient absorption and digestion (Turnbaugh and Gordon, 2009; Hehemann et al., 2010), detox and body defense (Relman, 2012), host immune system development (Turnbaugh and Gordon, 2009), etc. The mammalian gut hosts a diverse array of microbes, with the majority belonging to the Firmicutes and Bacteroidetes (Ley et al., 2008). This pattern holds correct across different populations, such as Koreans (Nam et al., 2011), Africans (De Filippo et al., 2010; Schnorr et al., 2014), Europeans and Americans (Qin et al., 2010), and Danes though not in the case of Chinese (Wu G. et al., 2014). The diversity of microorganisms can carry distinct consequences for diseases in various populations. For instance, individuals with type 2 diabetes from European and Chinese backgrounds exhibit varying compositions of gut microbiomes, with the Chinese population showing greater species diversity (Qin et al., 2012). Nonetheless, understanding the significant differences among these populations, considering factors like age, environment, and genetics, requires further investigation (Tai et al., 2015).

The gut microbiome harbors millions of diverse microorganisms, each contributing to its metabolic diversity and adaptability, with some genes potentially acquired from environmental bacteria (Hehemann et al., 2010; Qin et al., 2010). Notably, three primary enterotypes [Enterotypes are defined as clusters or patterns of microbial community composition in the gut microbiome that are driven by various factors such as diet, geography, host genetics, and lifestyle. Rather than discrete and stable classifications, enterotypes are now viewed as dynamic and context-dependent configurations of the gut microbiota. These configurations may shift over time in response to environmental changes, host health status, and other factors, reflecting the complexity and flexibility of the gut microbial ecosystem (Costea et al., 2018)]—Bacteroides, Prevotella, and Ruminococcus—have been identified in the human gut across diverse populations (Arumugam et al., 2011). These enterotypes, observed in Europeans, Japanese, and Americans, demonstrate a consistent presence in mice and chimpanzees (Moeller et al., 2012; Hildebrand et al., 2013; Wang et al., 2014). While the composition is mainly shaped by the host’s evolution, recent findings suggest that diet has a more significant impact on the metabolome than the microbiome. Discrepancies, especially regarding the prevalence of ecotypes like Ruminococcus, warrant further investigation considering factors such as sample size and variations in sampling methods (Arumugam et al., 2011; Wu et al., 2011; Huse et al., 2012; Zupancic et al., 2012; Gorvitovskaia et al., 2016; Liang et al., 2017). The gut microbiota comprises autochthonous microbes (Autochthonous refers to indigenous or native microbial species that are typically well-adapted to a specific environment, such as the gut) residing on the colonic mucosa epithelium and allochthonous microbes (Allochthonous refers to microbial species that are not native to a particular environment but are introduced from external sources) transiently passing through the lumen with digesta (Schnabl and Brenner, 2014). Distinguishing between these “residents” and “passengers” becomes crucial, as their roles are believed to differ significantly. The ratio of autochthonous to non-autochthonous microbes serves as a valuable indicator for assessing the progression of cirrhosis (Bajaj et al., 2014).

Diet and phylogeny are major contributors to the modification of the gut microbial community in various species, including mammals (Ley et al., 2008; Miyake et al., 2015). Genome-scale metabolic modeling reveals that changes in the host diet significantly alter the makeup of key human gut bacteria (eg. B. thetaiotaomicron) (Shoaie et al., 2013). Examples such as the impact of alcohol on intestinal microbiota emphasize the bidirectional relationship between diet and microbial composition, influencing host metabolism and related diseases (Mutlu et al., 2009; Chen et al., 2011; Yan et al., 2011; Mutlu et al., 2012; Queipo-Ortuño et al., 2012). Host genetics also play a crucial role in determining microbiome composition (Garrett et al., 2007; Maslowski et al., 2009; Benson et al., 2010; Brinkman et al., 2011; Lepage et al., 2011; Hashimoto et al., 2012; McKnite et al., 2012; Goodrich et al., 2014; Knights et al., 2014; Benson, 2015; Kubinak et al., 2015; Bonder et al., 2016a; Snijders et al., 2016; Igartua et al., 2017). The identification of shared susceptibility loci between inflammatory bowel disease and specific infectious organisms underscores the significance of exploring the interconnections among susceptibility, microbiome composition, and the development of the disease. This emphasizes the need to develop effective protocols for disease prevention by understanding these relationships (Kane et al., 2011; Henao-Mejia et al., 2012; Jostins et al., 2012; Knights et al., 2014). In the gut, Gram-negative bacteria produce lipopolysaccharide (LPS), a microbial product transported with chylomicrons (Balagopal et al., 2008; Jiang et al., 2009; Hofer et al., 2010; Marchetti et al., 2013). LPS acts as a potent stimulator of innate immunity, with its levels serving as important indicators for survival in peritoneal dialysis patients (Kwan et al., 2013). Similarly, trimethylamine (TMA) and its oxidation product, trimethylamine N-oxide (TMAO), impact patient morbidity, highlighting the far-reaching consequences of localized microbiome activity (Tang et al., 2017). These observations underscore the potential of using plasma levels of LPS and bacterial DNA as markers for both systemic inflammation and prognosis (Alexander and Rietschel, 2001).

The quantity of gut bacteria is greatly influenced by particular foods and dietary habits, which in turn affects health. High-intensity sweeteners, widely utilized as sugar substitutes, raise concerns based on animal studies. Despite regulatory agencies deeming them “generally recognized as safe,” sucralose, aspartame, and saccharin disrupt gut microbiota balance and diversity. Rats exposed to sucralose for twelve weeks displayed elevated amounts of total aerobic bacteria, Bacteroides, and Clostridium, along with a significantly higher fecal pH (Abou-Donia et al., 2008). Mice exposed to sucralose for six months exhibited increased expression of pro-inflammatory genes and altered fecal metabolites (Bian et al., 2017). Common food additives that impact gut flora include emulsifiers, which are included in processed meals. Mice given carboxymethylcellulose and polysorbate-80 displayed decreased microbial diversity, decreased Bacteroidales and Verrucomicrobia, and enrichment of inflammation-promoting Proteobacteria (Chassaing et al., 2015). Concerns extend to certain restrictive diets. Studies on vegan diets revealed variations in the gut microbe-produced serum metabolites, but only slight alterations in the bacterial communities (Wu G. et al., 2014). Gluten-free diets, recommended for gluten sensitivity or celiac disease, altered gut microbiota profiles in healthy individuals, potentially affecting useful microbial species (Bonder et al., 2016b). The low FODMAP diet, beneficial for irritable bowel syndrome, led to significant microbiota and metabolome changes (McIntosh et al., 2016; Gibson, 2017; Halmos, 2017; Bennet et al., 2018). Medications also modulate the composition of gut flora. An important research identified drugs such as progesterone, rupatadine, TNF-α inhibitors, and osmotic laxatives, as major modulators (Falony et al., 2016). Proton pump inhibitors and antibiotics, extensively used in humans and livestock, influence gut microbes, potentially contributing to obesity (Jackson et al., 2015; Blaser, 2016).

While clinical evidence is insufficient for clear recommendations, future studies on food additives, drugs, and dietary modifications should consider their effects on the gut microbiota. In medical contexts like cancer treatment and autoimmune disorders ( Figure 3 ), where microbiota changes impact responses, understanding these dynamics becomes crucial (Alexander et al., 2017). Animal studies also highlight the role of specific gut microbes in transforming compounds for protective effects, emphasizing the interconnectedness of diet, gut health, and overall well-being (Spanogiannopoulos et al., 2016).

The Streptococcus species, characterized by gram-positive, circular, or ovoid cells organized in chains or pairs, is commonly found in the nasopharynx and human stool (Lannes-Costa et al., 2021). Meta-transcriptomic study reveals that Streptococcus predominantly expresses the phosphotransferase system, suggesting their primary role in utilizing the carbohydrates that are present in the small intestine (Zoetendal et al., 2012). Streptococcus LJ-22 expresses β-glucuronidase activity, converting GL to 18β-glycyrrhetinic acid-3-O-β-D-glucuronic acid (GAMG), known for its anti-allergic properties. This compound has demonstrated anti-allergic potential against LPS-induced RAW264.7 cells (Guo et al., 2018). Furthermore, tannic acid degradation by Streptococcus gallolyticus subsp. Gallolyticus may contribute to colorectal cancer development by neutralizing its toxicity in the case of tumor cells (Oehmcke-Hecht et al., 2020). Streptococcus thermophilus GIM 1.321 demonstrates high β-glucosidase production, facilitating the breakdown of fructus anthocyanins into beneficial compounds like ferulic acid, CAA (caffeic acid), and CHA (chlorogenic acid) (Cheng et al., 2016). Administering CAA and CHA from these processes has shown the potential to lower blood pressure and provide antioxidant effects (Agunloye et al., 2019). Streptococcus strains, acting as commensals, pathogens, or opportunistic pathogens in the gut, require further exploration regarding their impact on the well-being of humans. Comprehending the way Streptococcus metabolizes natural compounds may help regulate the gut microbiota and improve the effectiveness of treatments. In-depth in vivo research is crucial to find out if focusing on bacteria that break down tannic acid could help develop more potent treatments for colorectal cancer. Overall, unraveling the intricacies of Streptococcus metabolism holds promise for advancing our comprehension of the gut microbiota and optimizing treatment interventions (Zhao et al., 2022).

Blautia species, prevalent in the anaerobic environments of mammalian guts and feces, exhibit notable probiotic properties in the biotransformation of natural products. Tremaroli and Bäckhed (2012) (Tremaroli and Bäckhed, 2012) highlight Blautia’s involvement in flavonoid processing, encompassing demethylation, O- and C-deglycosylation, and C-ring cleavage catalyzed by enzymes like O-glycosidase and β-glucosidases (Braune et al., 2016). Notably, Blautia sp. MRG-PMF1 demonstrates hydrolytic prowess, conver ting compounds like 5,7-dimethoxyflavone into chrysin and 5,7,4-trimethoxyflavone into apigenin. This strain also exhibits deglycosylation activity on various isoflavones, flavones, and flavonols, transforming them into their corresponding aglycones (Kim et al., 2014). In anaerobic environments, Blautia sp. MRG-PMF1 catalyzes curcumin to generate demethoxycurcumin, which has anti-inflammatory and anti-cancer characteristics and further metabolizes icariin into desmethylicaritin, which has estrogenic properties (Wu H. et al., 2016; Burapan et al., 2017; Hatamipour et al., 2019). Another strain, Blautia sp. AUH-JLD56, exclusively biotransforms arctiin or arctigenin into demethylated products with enhanced antioxidant potential (Liu et al., 2013). The creation of novel enzymes and bioactive metabolites is greatly encouraged by the increasing scholarly interest in Blautia’s involvement in the biotransformation and metabolism of herbal plants and functional foods (Meng et al., 2020).

Escherichia coli, a facultative anaerobic, non-sporous, gram-negative bacterium, predominantly resides in vertebrate intestines, playing a crucial role in glycosidase production for the transformation of exogenous substances (Foster-Nyarko and Pallen, 2022). Notably, E. coli strain HGU-3 synthesizes β-glucuronidase, facilitating the conversion of baicalin to baicalein, which exhibits superior anti-oxidant and anti-inflammatory potential (Han et al., 2016; Li D. et al., 2019). Additionally, certain E. coli strains, like DH10B, demonstrate high curcumin-converting activity through the expression of NADPH-dependent curcumin/dihydrocurcumin reductase (CurA) (Hassaninasab et al., 2011; Tan et al., 2014). The resulting dihydrocurcumin (DHC) and tetrahydrocurcumin (THC) show promising therapeutic benefits in hepatic steatosis, surpassing the effects of curcumin (Chen et al., 2018; Yu et al., 2018).

Moreover, E. coli strains Nu, MC, and WC-1 exhibit cinnamyl esterase properties, releasing hydroxycinnamic acids with in-vitro and in-vivo anticancer and antioxidant potential (Zhao et al., 2022). Understanding the genetic and biochemical aspects of E. coli opens avenues for synthesizing natural product derivatives with diverse health benefits. This knowledge is pivotal for exploring the potential of E. coli in producing compounds such as DHC (dihydrocaffeic acid) and THC (tetrahydrocurcumin), which effectively regulate triglyceride levels and demonstrate novel therapeutic advantages in hepatic steatosis. Overall, comprehending the capabilities of E. coli contributes to the development of natural product derivatives with diverse health benefits (Chen et al., 2018; Yu et al., 2018; Rodríguez-Daza et al., 2021; Candeliere et al., 2022).

The genus Eubacterium, a gram-positive constituent of the human gut microbiota, plays a vital part in metabolizing various substances (Mukherjee et al., 2020). Notably, E. ramulus, a well-studied flavonoid-degrading bacterium in the human intestine, produces enzymes like chalcone isomerase and flavanone-/flavanonol-cleaving reductase (Gall et al., 2014). These enzymes break down flavonoids into dihydrochalcone and its derivatives, known for their anti-inflammatory and antioxidant effects. E. ramulus strain wK1 further degrades flavonol quercetin and flavone luteolin, converting them into specific acids through reduction and ring fission (Zhao et al., 2022).

Another strain, E. cellulosolvens ATCC 43171T, is implicated in deglycosylating flavonoid O- and C-glucosides, exclusively catalyzing the deglycosylation of C-glucosides (Braune and Blaut, 2012; Braune et al., 2016). Additionally, Eubacterium L-8 exhibits the ability to hydrolyze terpenoid glycyrrhizin into 18β-glycyrrhetinic acid (18β-GA), which, in turn, demonstrates anti-inflammatory effects in preventing airway allergic inflammation (Liu et al., 2022). While these metabolic transformations highlight the potential health benefits of Eubacterium spp., it is emphasized that further in vivo studies are imperative to fully comprehend and harness the diverse advantages offered by this genus. This research could unlock opportunities to maximize the positive impact of Eubacterium strains on human health (Zhao et al., 2022).

The genus Lactobacillus, classified within the phylum Firmicutes, plays a crucial role in maintaining microbial balance and safeguarding gastrointestinal mucosal integrity (Dempsey and Corr, 2022). Certain Lactobacillus species are equipped with an array of metabolic enzymes, including α-rhamnosidases, tannase, and gallate decarboxylases, enabling them to transform exogenous substances (Reverón et al., 2017; Li B-C. et al., 2019; Ferreira-Lazarte et al., 2021).

L. rhamnosus NCTC 10302, possessing both β-glucosidase and α-rhamnosidase activities, demonstrates the ability to convert hesperetin-7-O-rutinoside and naringenin-7-O-rutinoside into their respective aglycones and 3-(phenyl) propionic acid through hydrolysis, ring fission, and dehydroxylation (Pereira-Caro et al., 2018). In a similar vein, L. plantarum expresses tannase, facilitating the hydrolysis of gallate and protocatechuate esters, ultimately producing gallic acid (Jiménez et al., 2014). Gallic acid, present in concentrations of 11.5–46 μg/ml, exhibits a protective part against LPS-induced inflammation and oxidative stress by suppressing the MAPK/NF-κB pathway and activating the Akt/AMPK/Nrf2 pathway (Tanaka et al., 2018).

Fang et al. witnessed the production of gallic acid and pyrogallol through the breakdown of gallotannins by gallotannin-metabolizing enzymes in L. plantarum WCFS1, suggesting potential prebiotic-probiotic assocaitions in preventing diet-induced metabolic diseases (Reverón et al., 2015; Fang et al., 2019). Additionally, Lactobacillus sp. Niu-O16 reduces daidzein to dihydrodaidzein with daidzein reductase activity, and dihydrodaidzein, at concentrations of 2.5–5 μM, supresses NF-κB activation and MAPK phosphorylation, therefore enhancing osteoporosis (Wang et al., 2007; Heng et al., 2019; Kim et al., 2019).

L. casei, L. plantarum, and L. acidophilus significantly impact the deglycosylation of piceid to resveratrol, enhancing bioavailability and bioactivity (Basholli-Salihu et al., 2016). Furthermore, feruloyl esterases from L. reuteri, L. helveticus, and L. fermentum hydrolyze chlorogenic acid, releasing caffeic acid (Santos et al., 2018). These results underscore the potential of Lactobacillus in health-improving pharmaceuticals and food products, but more investigation is required to clarify the fundamental transformation mechanisms (Zhao et al., 2022).

Bifidobacterium, a widely distributed genus within the Actinobacteria phylum, serves as one of the initial colonizers in the human gut microbiota (Satti et al., 2021; He et al., 2023). Key species include B. angulatum, B. breve, B. Catenulatum, B. adolescentis, B. longum etc, collectively constituting less than 10% of the adult human microbiome yet playing a crucial role in host health (Turroni et al., 2008; Turroni et al., 2009; Hidalgo-Cantabrana et al., 2018). Some Bifidobacterium species express feruloyl esterase, enabling the generation of phenolic acids. For example, B. animalis’s feruloyl esterase can hydrolyze chlorogenic acid into caffeic acid (CAA) (Raimondi et al., 2015). CAA (10–30 mg/kg) has demonstrated hepatoprotective effects in mice, preventing acetaminophen-induced acute liver injury by enhancing Nrf2 transcription (Raimondi et al., 2015; Pang et al., 2016). Bifidobacterium’s involvement in the gut facilitates the metabolism of various compounds, including glycosides, saponins, and flavanones (Zhao et al., 2022).

Specific strains of Bifidobacterium, such as B. longum R0175 and B. longum SBT2928, exhibit distinct metabolic activities. B. longum R0175 facilitates the production of 3-(3′-hydroxyphenyl) propionic acid and 3-(phenyl) propionic acid from hesperidin by ring-cleavage and demethylation (Pereira-Caro et al., 2018). B. longum SBT2928 contributes to bile acid metabolism by hydrolyzing main human and animal bile salts, suggesting a potential role in reducing cholesterol levels in vivo (Tanaka et al., 2000). Furthermore, B. breve ATCC 15700 demonstrates the production of β-glucosidase, which cleaves glycosides in ginsenoside Rd., generating deglycosylated ginsenoside compound K (Zhong et al., 2016; Zhang et al., 2019). Such metabolic properties position Bifidobacterium as a viable option for symbiotic establishment, utilizing its natural product synthesis capabilities for potential therapeutic applications (Zhao et al., 2022).

Diverse organisms, encompassing microorganisms, have long been recognized as prolific producers of secondary metabolites, also known as natural products (Law et al., 2020). Since the middle of the 20th century, the identification of these bioactive compounds, ranging from polyketides (PKs) to nonribosomal peptides (NRPs) and their hybrids, has been predominantly achieved through activity-based testing of cultivatable microorganisms, particularly Actinomycetes soil bacteria (Katz and Baltz, 2016). Over time, developments in molecular biology, DNA sequencing, and cultivation techniques have ushered in a new era, enabling the exploration of secondary metabolites from previously unculturable microbes (Lewis et al., 2010; Wilson and Piel, 2013; Sidebottom and Carlson, 2015; Browne et al., 2016). The impact of microbial natural products, as well as their semisynthetic derivatives, on human health, is profound, as they have emerged as vital sources for clinically relevant antibiotics, antifungals, immunosuppressants, anticancer agents, and other pharmaceuticals (Newman and Cragg, 2016). While the primary focus of natural product exploration has historically been medicinal usage, recent research has unveiled the intriguing ecological parts played by secondary metabolites in the organisms that produce them and their broader ecosystems, extending even to the human body (Crawford and Clardy, 2011; Cantley and Clardy, 2015; Wilson et al., 2017).

The microbiome, consisting of a myriad of microorganisms that inhabit the human body ( Figure 4 ), plays a crucial role in shaping human health and influencing various diseases. These microorganisms collectively harbor a gene pool that surpasses the human genome by a factor of 150 (Methé et al., 2012; Weinstock, 2012; Kho and Lal, 2018; Marsh et al., 2023; Walker and Hoyles, 2023). An analysis of data from the Human Microbiome Project (HMP), which includes genomic and metagenomic sequencing, has revealed that bacteria associated with humans possess the genetic machinery necessary to produce an extensive range of secondary metabolites (Donia et al., 2014). Despite this, the identities of the majority of such natural products remain undiscovered, and their functions are not fully comprehended. Investigating the ways through which these molecules impact interactions between hosts and microbes, as well as among different microbial species, could unveil factors that shape the impact of the microbiome on its host. This exploration holds the potential to yield targeted therapeutic options and may serve as a wellspring of innovative approaches to address human diseases. Few methods for uncovering natural products, and demonstrating their individual or collaborative use in deciphering the intricate metabolic interactions within the human microbiome have been presented (Wilson et al., 2017; Milshteyn et al., 2018).