Polyphenols are natural compounds with extensive biological activity and potential health-promoting properties. They exhibit antioxidant, anti-inflammatory, antihypertensive, anticancer, and antidiabetic effects (17–19). Most polyphenols in food typically exist in conjugated forms, which makes their molecular structure complex and their bioavailability low. During human digestion, the digestive enzymes in the stomach and small intestine cannot fully break down these polyphenols. As a result, only 5–10% of polyphenols are absorbed in the stomach and small intestine, while the remaining 90–95% enter the colon intact (20, 21). In the colon, polyphenols are metabolized by gut microbiota into monomeric forms of their glycosides or polymeric conjugates. These are then further degraded through reactions such as dehydroxylation, decarboxylation, and aromatic ring cleavage, eventually producing low molecular weight phenolic compounds that can be absorbed by intestinal cells (22). This metabolites influences gut ecology and human health (23). Numerous studies have demonstrated that long-term, moderate polyphenol intake can alter the gut microbiota, fostering a beneficial microbial environment and modifying the Firmicutes/Bacteroidetes ratio (12, 24), significantly improving human health.

Polyphenols are classified into flavonoids and nonflavonoids on the basis of their chemical composition and complexity (25). Flavonoids, a broadly researched polyphenol group, include diverse compounds such as flavones, flavanones, flavan-3-ols, flavonols, isoflavones, and anthocyanins (26, 27). Nonflavonoids include phenolic acids, particularly hydroxybenzoic acids (e.g., vanillic acid and gallic acid) and hydroxycinnamic acids (e.g., ferulic acid and caffeic acid) (28).

Dietary fiber, which consists of plant carbohydrates, is indigestible by human enzymes. Its chemical composition, physicochemical properties and physiological effects vary. Augmenting the amount of dietary fiber in one’s diet can potentially remodel the nutrient-dense environment of the gut, stimulating the growth of intestinal bacteria (74). Only specific gut microbiota constituents can metabolize dietary fiber through anaerobic fermentation, producing SCFAs, including acetate, propionate, and butyrate (14). These metabolites, in turn, influence the configuration, diversity, and abundance of the gut microbiota. Consequently, many research endeavors have focused on elucidating the effect of various dietary patterns on the gut microbiome.

Individuals consuming low-fiber diets often exhibit reduced microbial diversity. Research indicates that incorporating whole grain barley, brown rice, or both into the diets of volunteers enhances microbial diversity (75). For example, investigations have revealed that vegans and vegetarians possess notably greater diversity in their gut microbiota than omnivores (76). At the molecular level, fiber consumption enhances the growth of beneficial bacteria such as bifidobacteria and lactobacilli, which produce bioactive metabolites that regulate inflammation and gut barrier integrity by stimulating the production of mucins and tight junction proteins (77).

Consumption of high-fiber diets is more likely to result in Prevotella enterotype dominance in the gut microbiota (78). For example, children from Burkina Faso, who consumed a diet rich in starch, fiber, and plant proteins, had higher Prevotella counts than Italian children did (79). Similarly, a comparative study of Indian and Chinese adults revealed that Indians, whose diets contain more plant-based foods, had higher Prevotella counts compared to Chinese individuals (80). These results suggest a greater Prevotella to Bacteroides ratio in individuals consuming high-fiber or vegetarian diets, highlighting the significant impact of dietary habits on the gut microbiota composition.

High-fiber diets also impact the gut microbiota composition by enriching beneficial bacteria and depleting harmful bacteria. The previously mentioned study revealed that children residing in Burkina Faso, who adhered to diets rich in fiber, presented increased abundances of Bacteroidetes alongside decreased abundances of Firmicutes (79). This decrease in Firmicutes abundance has been correlated with efficient obesity prevention and management strategies (81). The molecular mechanisms behind this involve SCFA-mediated activation of peroxisome proliferator-activated receptors (PPARs), which regulate fatty acid storage and glucose metabolism, contributing to reduced fat accumulation and anti-inflammatory effects (82).

Furthermore, an additional study revealed that the consumption of fiber-rich brown rice markedly enriched the fecal populations of Enterococcus faecalis and Bifidobacterium adolescentis, bacteria known to confer gut health benefits, while simultaneously depleting detrimental microorganisms such as Clostridia, Bacteroides, Escherichia coli, and Eubacterium aerofaciens (83). Consequently, consumption of diets high in fiber can modulate the gut microbiota composition by decreasing Firmicutes levels, increasing the Bacteroidetes/Firmicutes ratio, and inhibiting the proliferation of harmful bacteria, ultimately fostering optimal gut health.

Prebiotics encompass a diverse array of compounds that remain undigested within the human gastrointestinal tract. These substances are naturally present in a plethora of plant sources, including onion, asparagus, garlic, chicory, ginger, oats, and wheat (84). Common prebiotics include inulin, fructooligosaccharides (FOSs), isomaltooligosaccharides (IMOs), and xylooligosaccharides (XOSs). The consumption of prebiotics fosters the proliferation of advantageous gut microbiota constituents, particularly lactobacilli and Bifidobacterium species (85). Inulin, for example, has been shown to enrich bifidobacteria populations and diminish the ratio of Gram-positive bacteria to Gram-negative bacteria (86). At the molecular level, prebiotics like inulin and FOS are fermented by gut microbes into SCFAs, primarily acetate and butyrate, which lower gut pH, inhibiting the growth of pathogenic bacteria (87). Additionally, SCFAs activate gut receptors such as GPR43, which plays a crucial role in regulating immune responses, particularly by reducing pro-inflammatory cytokine production and enhancing the function of regulatory T cells (88).

Some studies have reported a significant increase in the number of bifidobacteria in feces after oligofructose (OFS) consumption (89). Klancic et al. fed OFS to pregnant rats and reported an increase in the abundance of bifidobacteria and Collinsella in their offspring, which was associated with a reduced risk of obesity (90). Similarly, Cani et al. demonstrated that OFS increased the number of bifidobacteria in the intestinal tracts of obese mice, contributing to a reduction in adiposity and the inflammatory response (91). Further trials revealed that treating obese women with inulin/OFS prebiotics resulted in increased proportions of bifidobacteria and E. faecalis in the body. This effect was consistent with a reduction in fat mass and serum lipopolysaccharide (LPS) levels, indicating a decrease in inflammation (92). This reduction in LPS-driven inflammation is important, as LPS is known to activate Toll-like receptor 4 (TLR4), which triggers pro-inflammatory signaling pathways and insulin resistance (93). These discoveries imply that the consumption of prebiotics is crucial for human wellbeing, as they aid in the restoration of the gut microbiota balance, promote the proliferation of beneficial bacteria, contribute to the prevention and management of obesity, and reduce inflammatory responses.

SCFAs are fatty acid compounds with 1–6 carbon atoms (94), produced by the fermentation of dietary fiber by the gut microbiota (95). SCFAs are essential for energy production, lipogenesis, gluconeogenesis, and cholesterol synthesis (96). SCFAs including acetate, propionate, and butyrate, play vital roles in human health by regulating critical biological processes (97). Typically, the molar ratio of acetate: propionate: butyrate is approximately 60:20:20 (98). However, different SCFAs are metabolized by different bacteria, resulting in varying proportions (99). For instance, Bacteroides produce propionate; Akkermansia, Bifidobacterium, Prevotella, and Bacteroides produce acetate; and Faecalibacterium produces butyrate (100). There is a clear link between SCFA levels and the microbiota composition. The fermentation process increases SCFA concentrations in the gut lumen, lowering the colonic pH and inhibiting the growth of Gram-negative Enterobacteriaceae (15). SCFAs, particularly butyrate, serve as beneficial metabolic substrates for energy homeostasis in epithelial cells and are an important source of energy for colonocytes (101, 102). Butyrate stimulates the normal growth and differentiation of epithelial cells, maintains intestinal barrier function, and reduces apoptosis (103, 104).

At the molecular level, SCFAs exert their effects through several mechanisms. SCFAs can enter the bloodstream and activate various G protein-coupled receptors (GPCRs), mainly GPR41 (also known as FFAR3), GPR43 (FFAR2), and GPR109A (HCAR2) (82, 105). Activation of GPR41 and GPR43 on enteroendocrine cells stimulates the release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), which regulate appetite and glucose homeostasis (106). GPR109A is specifically activated by butyrate and niacin, affecting lipid, glucose, and cholesterol metabolism (107). For example, acetic acid and propionic acid stimulate the production and secretion of GLP-1 through the activation of GPR43 in the intestinal tract, promoting insulin release and inhibiting glucagon secretion (108). Butyrate independently induces the expression of key intestinal gluconeogenesis genes, such as phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC), via histone acetylation and activation of the cAMP response element-binding protein (CREB) (109). Additionally, SCFAs protect the gut from infection and inflammation-induced damage through GPR41-mediated promotion of interleukin-22 (IL-22) production by innate lymphoid cells (ILCs) (110).

Moreover, SCFAs inhibit histone deacetylases (HDACs), leading to increased histone acetylation and altered gene expression in immune cells (111). This epigenetic regulation results in anti-inflammatory effects by suppressing the production of pro-inflammatory cytokines such as TNF-α and IFN-γ (112). Butyrate also promotes the differentiation of regulatory T cells (Tregs) by enhancing the acetylation of the Foxp3 gene promoter, which is essential for Treg development (113). Studies have shown that dietary interventions, such as the addition of legumes to rat diets, can increase SCFA production and the abundance of butyrate-producing bacteria. This increase in butyrate levels has been associated with reduced body weight, lower body fat, and improved insulin sensitivity.

Bile acids are the end products of cholesterol metabolism and are amphipathic steroid molecules, including primary and secondary bile acids, which are involved in the digestion and absorption of dietary fats and fat-soluble vitamins (114). Primary bile acids, such as cholic acid (CA) and chenodeoxycholic acid (CDCA), are synthesized from cholesterol. Once transported to the intestine, the gut microbiota converts primary bile acids into secondary bile acids through deconjugation and 7-dehydroxylation, resulting in the production of compounds such as deoxycholic acid (DCA) and lithocholic acid (LCA) (115, 116). In humans, bile acids are converted in four different ways, including deconjugation, dehydroxylation, oxidation, and differential isomerization (117), although the specific intestinal bacteria responsible for the production of bile acid metabolites have not been fully elucidated.

The intestinal microbiome governs the constitution of bile acids, subsequently exerting a substantial effect on the configuration of the human gut microbiota. These bile acids, which possess detergent-like characteristics, are capable of disrupting bacterial cellular structures and remodeling microbial assemblages by constraining the proliferation or persistence of specific bacterial taxa. For example, investigations have demonstrated that increased bile acid concentrations in mice promote the proliferation of potential pathogens, such as Bilophila and Desulfovibrio, concurrently diminishing the abundance of beneficial bacteria such as Ruminococcus, lactobacilli, and Roseburia (118). Interestingly, Gram-positive bacteria are more sensitive to bile acids compared to Gram-negative bacteria, with bile acids favoring the growth of Gram-negative bacteria (115, 119).

Furthermore, bile acids act as signaling molecules by activating specific receptors, thereby regulating metabolism and immune responses. Bile acid signaling cascades encompass an array of receptors, namely the nuclear hormone receptor farnesoid X receptor (FXR), the G protein-coupled bile acid receptor TGR5 (also known as GPBAR1), and the pregnane X receptor (PXR), each contributing to the intricate regulatory network governing bile acid homeostasis (120, 121). FXR is distributed in various tissues, including the liver and intestines. Upon activation by bile acids, FXR regulates the expression of genes involved in bile acid synthesis, lipid metabolism, and glucose homeostasis (122). In the intestine, FXR activation induces the expression of fibroblast growth factor 19 (FGF19 in humans, FGF15 in mice), which acts in an endocrine manner to suppress hepatic bile acid synthesis via the small heterodimer partner (SHP) pathway (123). FXR also enhances the intestinal barrier function by increasing the expression of tight junction proteins and antimicrobial peptides, thereby inhibiting bacterial overgrowth and translocation (124). This interaction helps shape the gut microbiota composition indirectly through FXR signaling. For instance, mice lacking FXR showed disruption of intestinal epithelial barrier function and increased susceptibility to bacterial translocation (125).

Moreover, secondary bile acids such as DCA and LCA can activate FXR and TGR5 receptors, influencing metabolic processes. The G protein-coupled bile acid receptor TGR5 is expressed in immune cells, brown adipose tissue, and muscle (126), and is involved in immune regulation, energy expenditure, and glucose metabolism (127, 128). Activation of TGR5 by bile acids leads to increased intracellular cyclic adenosine monophosphate (cAMP) levels, stimulating energy expenditure and thermogenesis in brown adipose tissue via the type 2 deiodinase (D2)-mediated conversion of thyroxine (T4) to triiodothyronine (T3) (122).

Among these, LCA and its taurine conjugate, taurolithocholic acid (TLCA), are the most potent ligands for TGR5 (129, 130). The activation of TGR5 signaling by bile acids regulates GLP-1 secretion from enteroendocrine L-cells, affecting insulin secretion and blood glucose levels (131). Another study found that bile acid metabolites can increase energy expenditure in brown adipose tissue and generate heat via TGR5-mediated pathways (122). Additionally, bile acids modulate immune responses by interacting with receptors on immune cells. For example, TGR5 activation on macrophages inhibits NF-κB signaling, reducing the production of pro-inflammatory cytokines (132). This immunomodulatory effect contributes to the anti-inflammatory properties of bile acids.

Tryptophan is an essential amino acid found in dietary proteins, and is sourced from foods like oats, milk, tuna, and peanuts. The intestinal microbiota engages in tryptophan metabolism, yielding a plethora of metabolites via three distinct routes: (1) direct conversion of tryptophan by gut microorganisms into several molecules, a subset of which function as ligands for the aryl hydrocarbon receptor (AhR), as previously reported (133); (2) the serotonin biosynthesis pathway (134); and (3) the kynurenine metabolic cascade (135). Indole, indole derivatives, and tryptamine are the major tryptophan metabolites in the gut. Notably, however, different bacteria produce different tryptophan metabolites. For instance, Peptostreptococcus converts tryptophan to indolepropionic acid (IPA) and indole-3-propionic acid (IPA) (136), whereas Bacteroides and Clostridium produce skatole from indole-3-acetic acid (IAA) (137). Clostridium sporogenes converts tryptophan into IAA and IPA (138, 139), which play critical roles in maintaining gut homeostasis.

Tryptophan metabolites enhance intestinal epithelial barrier function by increasing the expression of genes involved in maintaining epithelial cell structure and function (140). At the molecular level, many tryptophan metabolites act as ligands for AhR, a transcription factor involved in the regulation of immunity and intestinal barrier function (141). For example, research has shown that IPA activates AhR, promoting the differentiation of goblet cells and mucus production, thereby strengthening the intestinal epithelial barrier and reducing inflammation (139). IPA activates PXR receptors to inhibit intestinal inflammation and enhance intestinal barrier function (142). Activation of PXR by IPA leads to the suppression of NF-κB signaling and downregulation of pro-inflammatory cytokines such as IL-6 and TNF-α (143). The anti-inflammatory, barrier-maintaining effects of IPA are mediated by the activation of either PXR or AhR. AhR senses a variety of intestinal signals that are critical for immune responses at barrier sites (141, 144).

PXR plays a crucial role in intestinal inflammation and neoplasia, indicating that metabolites derived from tryptophan regulate the development of colitis and colorectal cancer (CRC). AhR activation increases the production of IL-22 by innate lymphoid cells and Th17 cells, which promotes epithelial regeneration and enhances antimicrobial defense, reducing colitis susceptibility (139). In vitro studies have shown that tryptophan metabolites can also achieve anti-inflammatory effects by inhibiting histamine production in macrophages (145). Additionally, some tryptophan metabolites (e.g., nicotinic acid) can act as GPR35 and GPR109A agonists to induce colonic Treg differentiation (146). These G protein-coupled receptors, when activated, promote the expansion of regulatory T cells and the production of anti-inflammatory cytokines like IL-10, which are critical for limiting intestinal inflammation (147). However, more research is needed to fully elucidate the molecular mechanisms underlying the effects of tryptophan metabolites.

IBD, an umbrella term including ulcerative colitis (UC) and Crohn’s disease (CD), represents a protracted gastrointestinal malady characterized by an exaggerated immunological reaction toward the intestinal microbiota. This hyperactive immune response results in relentless inflammatory processes and disrupts the delicate microbial equilibrium within the gut (149). The gut microbiota in IBD patients shows a notable depletion of Firmicutes and an increase in Enterobacteriaceae and Proteobacteria. Various dietary bioactive compounds and their metabolites significantly influence the gut microbiota, exhibiting potential anti-inflammatory effects (9). Nonetheless, the heterogeneity of study designs and patient populations necessitates cautious interpretation of these findings.

Green tea, which is rich in polyphenols, has demonstrated anti-inflammatory properties. Studies in mice have shown that green tea consumption increases the abundance of beneficial bacteria such as Akkermansia and lactobacilli, while reducing the abundance of potential pathogens such as Turicibacter and Romboutsia (150). Additionally, green tea polyphenols downregulate the TLR4/MyD88/NF-κB inflammatory pathway, exerting an anti-inflammatory effect. However, these results are primarily from animal studies, and human clinical trials are limited. Factors such as bioavailability and individual differences in gut microbiota composition may affect the efficacy of green tea polyphenols in humans (57, 58).

Berries, especially blueberries, are rich in anthocyanins and have shown promise in reducing inflammation in colitis models. Supplementation with blueberry extract in colitis-afflicted mice has been shown to reduce the disease activity index (DAI) (151). Treating experimentally induced colitis in mice with blueberry anthocyanin extract has been shown to promote the production of IL-10 and decrease the levels of nitric oxide (NO), myeloperoxidase (MPO), IFN-γ, IL-12, and TNF-α, indicating the potential anti-inflammatory properties of berry compounds (152). However, variations in study methodologies, such as differences in anthocyanin doses, extraction methods, and animal models, can lead to inconsistent results. Some studies have not observed significant effects, suggesting that more standardized research is needed (153).

Additionally, specific gut microbial metabolites significantly impact the progression of IBD. SCFAs inhibit the activity of NF-κB and HDACs, reducing the levels of proinflammatory cytokines and thereby exerting anti-inflammatory effects (112, 154). Furthermore, SCFAs, especially butyrate, can enhance anti-inflammatory effects by inhibiting HDACs and further suppressing the production of proinflammatory cytokines such as IL-12 (155). Among SCFAs, butyrate is particularly notable for its ability to strengthen the intestinal barrier and modulate immune responses (103, 156). However, the effectiveness of SCFAs may vary depending on individual microbiota composition and the site of inflammation. It is noteworthy that a reduction in the abundance of SCFA-producing bacteria in the gut can adversely affect IBD. A study by Vernia et al. revealed that oral administration of butyrate can increase the efficacy of mesalamine in treating active UC, indicating that a decrease in butyrate-producing bacteria is detrimental to alleviating intestinal inflammation in patients with UC (157). Conversely, some patients may not respond to butyrate supplementation, possibly due to differences in gut microbiota or disease pathology (158).

The bile acid receptor FXR is related to IBD, and FXR agonists can alleviate DSS-induced colitis (125). Research has shown that, compared with healthy individuals, IBD patients have significantly lower serum tryptophan levels, with CD patients having even lower levels than UC patients do (159). Plasma tryptophan concentrations are negatively correlated with the severity of IBD. In both mouse models and IBD patients, dietary tryptophan deficiency exacerbates colitis (160). Therefore, dysregulated tryptophan metabolism in IBD patients accelerates disease progression. However, the exact mechanisms and therapeutic potential of modulating tryptophan metabolism require further investigation.

Currently, strategies for treating IBD using bioactive compounds have made some progress in clinical practice. For example, curcumin, a bioactive ingredient, has been found in studies on IBD patients to significantly reduce intestinal inflammation through the inhibition of the NF-κB signaling pathway and the activity of p38 mitogen-activated protein kinase (MAPK) (161). Additionally, the combination of curcumin with traditional medications has shown efficacy in pediatric IBD patients, with no significant clinical side effects reported (162). Furthermore, supplementing with probiotics such as Bifidobacterium and lactobacilli can modulate gut immunity and reduce intestinal inflammation, providing health benefits (163). However, there is still a lack of sufficient clinical evidence on the efficacy of probiotics in IBD patients. Future efforts should focus on translating findings from animal studies into clinical applications to offer more effective treatment options for IBD patients.

CRC ranks among the most lethal diseases globally and has a high mortality rate. Its incidence increases rapidly with age, although the reasons for this increase remain unclear (153). Numerous risk factors contribute to CRC, including age, IBD, obesity, smoking, dietary habits, and genetics (158). Current treatments for CRC are inadequate because of their limited efficacy, their potential side effects, the development of resistance to chemotherapy, and disease recurrence. However, accumulating research indicates that dietary bioactive compounds and gut metabolites can alleviate CRC (164).

Polyphenol metabolites play a critical role in CRC management by regulating the gut microbiota and directly limiting the growth and proliferation of CRC cells (10). Studies have shown that administering a flavonoid mixture of apigenin and Epigallocatechin-3-gallate (EGCG) to CRC patients reduces cancer recurrence rates (165). However, these findings are based on small-scale studies, and larger clinical trials are necessary to validate the efficacy of these compounds. Moreover, some studies suggest that high doses of EGCG may have pro-oxidant effects and could potentially promote carcinogenesis under certain conditions (71, 166). Additionally, green tea consumption decreases the abundance of Fusobacterium, a bacterium strongly associated with CRC (166). The catechin EGCG in green tea induces apoptosis and cell cycle arrest in colon cancer HCT-116 cells, demonstrating its anticancer potential (167). Furthermore, in vitro research suggests that green tea polyphenol metabolites inhibit the proliferation of HCT-116 cells (168), indicating that these metabolites may exert anticancer effects, although further research is needed to elucidate the underlying mechanisms. Nevertheless, the bioavailability of polyphenols is limited, and their metabolic transformation by gut microbiota can produce metabolites with different activities, complicating their therapeutic use.

SCFAs, such as propionate, butyrate, and acetate, are produced by the fermentation of dietary fiber by the gut microbiota. A diet low in dietary fiber is associated with a higher risk of CRC development (169). The antitumor effects of dietary fiber are closely linked to these SCFAs. Butyrate, in particular, influences CRC progression through various mechanisms. It accelerates histone acetylation, promotes the proliferation of normal epithelial cells, and promotes CRC cell death while inhibiting their proliferation (170). Additionally, butyrate impedes CRC cell angiogenesis, metastasis, and survival by suppressing Sp1 transcription activation (171). It also induces apoptosis by inhibiting the Wnt/β-catenin signaling pathway (172) and enhances anticancer treatment efficacy by modulating cytotoxic CD8+ T cell immunity (173). However, some studies have suggested that butyrate might promote cancer cell survival under hypoxic conditions, indicating a potential dual role depending on the tumor microenvironment (167, 168). Thus, butyrate, as a gut microbial metabolite, plays a pivotal role in preventing CRC development. Comparatively, butyrate appears to have stronger anticancer effects among SCFAs, but the context of its action is important. In addition, propionate plays an important role in CRC. Propionate can induce histone acetylation to inhibit the proliferation of colon cancer cells (174). Luu et al. reported that propionate and butyrate can exert antitumor effects by promoting the expression of genes associated with Tc17 cells and CD8+ cytotoxic T lymphocytes (CTLs) (175).

Bile acid derivatives, including ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), possess the capability to stimulate TGR5 activity, thereby exhibiting anti-inflammatory activity via the augmentation of signaling pathways and the subsequent suppression of proinflammatory cytokine generation, which is mediated by the Toll-like receptor 4 (TLR4) signaling cascade (176). However, secondary bile acids like deoxycholic acid (DCA) have been implicated in promoting CRC by inducing DNA damage and inflammation (177). This suggests that bile acids can have both protective and harmful effects, depending on their specific forms and concentrations. Megna et al. reported that indole-3-methanol (I3C) promotes the expression of the tumor suppressor protein p53 and activates apoptotic factors, leading to apoptosis in colon cancer cells (178). Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme initiating the kynurenine pathway. It has been shown that kynurenine reduces tumor-infiltrating CD8+ cells and mediates the immune evasion of tumor cells (179). Therefore, modulating tryptophan metabolism via the kynurenine pathway could be considered in the future for the treatment of colorectal cancer.

Harmful microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO) and secondary bile acids, can induce tumor formation by damaging DNA and abnormally activating intracellular oncogenic signaling pathways. For example, secondary bile acids promote the PKC-p38 MAPK signaling pathway, accelerating the progression of colorectal cancer (CRC) (177). Additionally, a case–control study demonstrated a positive correlation between TMAO levels and CRC risk (180), though direct evidence confirming TMAO’s role in promoting CRC is still lacking. Some studies have not found a significant association between TMAO levels and CRC risk, indicating conflicting results (180). Further research is needed to clarify its carcinogenic mechanisms.

Currently, the clinical application of bioactive compounds and metabolites in CRC treatment is limited. Some phytochemicals, such as curcumin and resveratrol, have been investigated in clinical trials for their anticancer properties, but results have been mixed due to poor bioavailability and variability in patient responses (164). Prebiotics and probiotics have been proposed as adjunct therapies to modulate the gut microbiota and reduce CRC risk. However, clinical evidence is still emerging, and more large-scale, well-designed studies are needed to establish their efficacy and safety (163). Future therapies may involve personalized approaches targeting specific microbiota compositions and metabolic profiles. The use of microbiota-derived metabolites as biomarkers for CRC risk and as therapeutic agents is a promising area of research. Advances in drug delivery systems may enhance the bioavailability of bioactive compounds, improving their clinical utility.

CVDs, including hypertension, atherosclerosis, and heart failure, have high mortality rates globally. Accumulating research indicates that the gut microbiota and its metabolites significantly influence the development and progression of CVD. Dietary interventions can induce beneficial changes in gut microbiota, thereby preventing CVD (181). For example, a diet rich in plant-based products have been shown to lower oxidized low-density lipoprotein cholesterol levels in patients with ischemic heart disease. This dietary pattern also alters the relative abundance of specific gut bacteria, particularly those in the Ruminococcaceae and Barnesiella genera, and their metabolites, reducing the risk of CVDs (182). Resveratrol exerts a cardioprotective effect by inhibiting the TLR4/NF-κB signaling pathway in rats, thereby reducing the risk of cardiovascular disease (183). In addition, Hobbs and colleagues conducted a study on patients with hypercholesterolemia using supplements such as Omega-3 fatty acids, resveratrol, and flavonoids. The results showed a reduction in both total cholesterol and low-density lipoprotein (LDL) levels, which is of great significance for the prevention and treatment of cardiovascular diseases (184). Among bioactive compounds, resveratrol appears to have strong effects, but its low bioavailability limits its therapeutic potential. Conflicting evidence exists regarding the efficacy of polyphenol supplements in reducing cardiovascular risk, with some studies showing minimal benefits (185). Methodological limitations include small sample sizes, short intervention periods, and variations in study populations.

SCFAs, including propionate, butyrate, and acetate, are crucial gut metabolites that inhibit CVD progression. SCFAs promote the release of the hormones peptide YY (PYY) and GLP-1, which lower blood pressure and inhibit atherosclerosis (186). Propionate, in particular, has been shown to have cardioprotective properties by activating GPR41 signaling in vascular endothelial cells, leading to moderate vasodilation and reduced blood pressure (187). However, the exact mechanisms are not fully understood, and individual variability in gut microbiota composition may influence outcomes.

Current therapies focus on lifestyle modifications and pharmacological interventions. While some supplements like omega-3 fatty acids and flavonoids have been used, the clinical evidence supporting their efficacy is mixed (184). Future prospects include developing therapies that modulate the gut microbiota to enhance the production of beneficial metabolites like SCFAs. Personalized nutrition based on individual microbiota profiles may become a valuable tool in CVD prevention and management.

Obesity primarily results from the accumulation of adipose tissue, leading to an inappropriate increase in body weight relative to height. This condition is typically associated with excessive fat accumulation, insulin resistance, and chronic low-grade inflammation (188). Research indicates that, compared with healthy individuals, obese individuals exhibit reduced diversity and richness in their gut microbiota. There is a notable decrease in the abundance of beneficial bacteria such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bacteroides, alongside a significant increase in the abundance of Firmicutes (189). Gut microbiota plays a role in obesity pathogenesis, but findings are sometimes conflicting (188, 189). Methodological limitations such as differences in diet, genetics, and lifestyle factors make it challenging to establish causality.

SCFAs, which are produced as metabolites by the gut microbiota, regulate the secretion of GLP-1 and PYY via theGPR41 and GPR43 receptors (108). These factors can suppress appetite, increase energy expenditure, and help maintain energy balance, thus preventing obesity (190). Additionally, SCFAs promote the production of thermogenic proteins (PPARγ, PGC1α, and UCP1) and lipid oxidation-related proteins (CPT-I and UCP2), thereby increasing energy expenditure and lipid oxidation to prevent obesity (144). Conversely, a high-fat diet leads to a reduction in SCFA levels (191), whereas a low-fat diet has been shown to increase the abundance of beneficial bacteria such as Faecalibacterium and Blautia, which are beneficial for lipid metabolism (192). Butyrate and propionate appear to have strong effects in promoting lipid oxidation and energy expenditure (144). However, some studies report that elevated SCFA levels may contribute to increased energy harvest from the diet, potentially promoting obesity (82). This paradox highlights the need for a deeper understanding of SCFA functions and their interactions with host metabolism.

Probiotic and prebiotic interventions have been explored to modulate the gut microbiota in obesity management (192). However, clinical trials have yielded mixed results, and long-term efficacy remains uncertain. Future therapies may focus on personalized approaches, considering individual microbiota compositions to enhance weight loss strategies.

Diabetes is a systemic metabolic disorder characterized by hyperglycemia, arising from either reduced insulin secretion or decreased insulin sensitivity (193). T2DM is the most prevalent form, accounting for 90% of cases, and is characterized by decreased insulin secretion and insulin resistance (194). Increasing evidence suggests that gut microbiota dysbiosis is closely associated with T2DM development. Studies have shown that T2DM patients exhibit reduced gut microbiota diversity (195), with a marked decrease in beneficial bacteria such as bifidobacteria and Akkermansia, and an increase in the abundance of harmful bacteria such as Dallella (196). Thus, targeting the gut microbiota may present a novel therapeutic approach for treating T2DM and related metabolic disorders.

The Mediterranean diet, which is rich in polyphenols, has been shown to promote the proliferation of beneficial bacteria such as Bacteroides and Clostridium, thereby assisting in weight management and glycemic control (197). In an animal model of diabetes, a cocoa-rich diet increased the abundance of acetate-producing bacteria, particularly Blautia, while reducing the abundance of Enterococci and lactobacilli, aligning the gut microbiota composition more closely with that of lean rats (198). Quercetin, a bioactive compound found in plants, has been shown to improve lipid profiles, lower serum glucose levels, increase insulin levels, and reduce oxidative stress in diabetic rats (199). The combined administration of isoquercitrin (a quercetin glucoside) and inulin (a nondigestible polysaccharide) modulates the composition of the colonic microbiota, thereby assisting in the maintenance of glycemic balance and reducing insulin resistance (200). Polyphenols such as quercetin and resveratrol have shown potential in improving insulin sensitivity and glucose metabolism (199). Resveratrol appears to have strong effects, but its clinical efficacy is limited by poor bioavailability (68). Conflicting results exist, with some studies showing no significant benefits (185).

Furthermore, changes in the gut microbiota can lead to alterations in the levels of gut metabolites. Consumption of dietary fiber increases the abundance of SCFA-producing bacteria, thereby increasing gut SCFA levels. This promotes GLP-1 secretion by intestinal cells, which in turn increases insulin levels. SCFAs also improve glycemic control and delay the progression of T2DM by inhibiting NF-κB activation and IκBα degradation, thereby reducing the expression of proinflammatory cytokines (201). In addition to SCFAs, bile acids activate FXR and regulate GLP-1 secretion (131), and the tryptophan metabolite indole also regulates the secretion of GLP-1 (202).

Dietary interventions, including high-fiber diets and polyphenol-rich foods, are recommended for diabetes management (181). However, supplementing specific bioactive compounds has not become standard practice due to inconsistent clinical evidence. Future therapies may involve targeting gut microbiota to enhance SCFA production or using synthetic SCFA analogs.