Fermented Tea and Cognitive Dysfunction in Diabetes: A Novel Perspective on the Gut‐Brain AXIS

Fermented tea represents a significant category within global tea production systems. It is characterized by distinctive flavor profiles and aromatic properties that appeal to consumers, alongside documented health benefits that have garnered substantial research interest (Gu et al. 2017; Akinrinmade et al. 2017). The fermentation process involves diverse microbial communities, primarily comprising Aspergillus niger, Penicillium spp., various yeast species, and others (Tang et al. 2019; Gaggìa et al. 2018). Based on fermentation degree, teas are systematically classified into four categories: micro‐fermented, semi‐fermented, fully fermented, and post‐fermented tea (Jakubczyk et al. 2023). This established microbial basis and classification framework provide essential context for investigating fermented tea's potential bioactive modulation of the gut‐brain axis in diabetic cognitive dysfunction.

Micro‐fermented tea includes yellow tea (Hayat et al. 2015) and white tea, characterized by minimal oxidation. This classification signifies that white tea experiences minimal fermentation. Limited fermentation preserves native polyphenolic compounds, resulting in delicate sensory profiles. Scientific evidence indicates these teas exhibit antioxidant, anti‐inflammatory, and antibacterial properties (Li et al. 2022; Luo et al. 2020). The preserved native polyphenols and associated bioactive properties in micro‐fermented teas position them as key candidates for investigating gut microbiota modulation and its downstream effects on the gut‐brain axis in diabetic contexts.

Oolong tea represents the typical semi‐fermented variant (Tung et al. 2022). Partial oxidation converts polyphenols into thearubigins, yielding sensory characteristics intermediate between green and black teas. Documented health effects include neurostimulation, lipid metabolism modulation, and antioxidant activity (Tung et al. 2022; Chai et al. 2020). These distinctive biochemical transformations and multifaceted bioactivities position oolong tea as a compelling subject for investigating gut‐mediated polyphenol metabolites and their potential neuromodulatory effects within the diabetic gut‐brain axis.

Fully fermented tea, characterized by an extensive oxidation level of 80%–90%, encompasses brick tea and black tea (Liu et al. 2023; Lei et al. 2024). Polyphenol oxidation generates theaflavins and thearubigins, responsible for the characteristic reddish infusion color and robust flavor. Bioactive compounds in these teas demonstrate antioxidant capacity, antihypertensive effects, and cholesterol‐lowering potential (Pan et al. 2023; Gao, Wang, et al. 2023; Takemoto and Takemoto 2018). The high oxidation‐derived theaflavins and thearubigins in fully fermented teas represent critical bioactive candidates for exploring microbial metabolite‐mediated signaling pathways along the gut‐brain axis in diabetic cognitive impairment.

Post‐fermented tea is a distinct processing category that involves microbial solid‐state fermentation ("wet piling") of processed green tea leaves under controlled humidity and temperature (Gao, Fu, et al. 2023). Representative varieties include Anhua black tea, Hubei Qingzhuan tea, Sichuan Tibetan tea, Guangxi Liubao tea, and Yunnan Pu'er tea (Tang et al. 2019; Assumpção et al. 2022). Additionally, fermented tea‐based beverages such as kombucha, Japanese kocha‐kin, Korean insam‐cha (ginseng tea), and Russian ivan‐chai exhibit unique fermentation dynamics and health benefits attributed to microbial transformations (Xu et al. 2019; Cheng et al. 2022; Júnior et al. 2022; Unban et al. 2019). The complex microbial consortia and biotransformation processes inherent to post‐fermented teas and traditional beverages offer a unique reservoir for investigating gut microbiota modulation and microbial metabolite‐mediated communication along the gut‐brain axis in diabetic pathology.

Fermentation of tea not only modifies its flavor and color but also generates diverse bioactive compounds with significant health‐promoting properties. The primary bioactive constituents of fermented tea include polyphenols, amino acids, caffeine, vitamins, minerals, and microbial metabolites (Jakubczyk et al. 2023; Banerjee and Chatterjee 2014; Gao, Wu, et al. 2022; Hu et al. 2021). These components act synergistically to confer unique health benefits, including antioxidant properties, anti‐inflammatory effects, as well as modulation of blood glucose and lipid profiles, among others (Jeong et al. 2021; Huang et al. 2019; Assad et al. 2023). This biochemical synergy, particularly microbial metabolite‐driven bioactivity, establishes fermented tea as a compelling modulator of gut‐brain crosstalk, warranting mechanistic investigation into its therapeutic potential for diabetic cognitive dysfunction.

Polyphenolic Compounds: Polyphenols represent a major class of bioactive compounds in fermented tea, predominantly comprising catechins, theaflavins, and thearubins (Musial et al. 2020; Rothenberg et al. 2018; Tong et al. 2019; Chen et al. 2019; Chen and Yang 2020). While catechins are abundant in unfermented green tea, enzymatic oxidation during fermentation converts a proportion of catechins into theaflavins and thearubins. This transformation alters the organoleptic properties of tea (e.g., flavor and color) and enhances its antioxidant capacity (Mostafa et al. 2022; Liu, Dai, et al. 2020; Sergi 2022). Theaflavins and thearubins exhibit superior free radical scavenging activity, mitigating oxidative stress and protecting cellular integrity (Liu et al. 2023; Wang et al. 2023; Xu et al. 2024). The fermentation‐enhanced antioxidant potency of theaflavins and thearubigins positions these polyphenolic metabolites as key mediators for targeting oxidative stress‐induced neuroinflammation in diabetic cognitive impairment via the gut‐brain axis.

Amino acids: Fermented tea contains elevated levels of amino acids, notably theanine (Türközü and Şanlier 2017). Theanine, a tea‐specific amino acid, demonstrates neuroactive properties, including stress reduction and sleep quality improvement (Nobre et al. 2008; Zhu et al. 2016). Although fermentation may reduce theanine content, its bioactivity toward the central nervous system is retained.

Caffeine: Fermentation reduces caffeine concentration in tea; however, residual caffeine retains mild stimulatory effects that enhance alertness, focus, and cognitive function (Fortunato et al. 2024; Gramza‐Michałowska 2014). While moderate caffeine intake is generally safe, caffeine‐sensitive individuals should exercise caution (Hayat et al. 2015). This nuanced caffeine profile, modulated by fermentation yet retaining cognitive benefits, positions it as a key variable in studying gut‐brain axis communication, particularly regarding microbiota‐mediated caffeine metabolism and its impact on diabetic neurocognition.

Vitamins and Minerals: Fermented tea provides essential vitamins (e.g., vitamin C, B‐complex vitamins) and minerals (e.g., potassium, magnesium), which support physiological functions, immune regulation, metabolic processes, and electrolyte homeostasis (Tang et al. 2019). These nutrients play a crucial role in supporting the normal physiological functions of the body, enhancing the immune response, facilitating metabolic processes, and ensuring proper electrolyte balance.

Other Bioactives: Additional beneficial compounds in fermented tea include flavonoids and polysaccharides, which exhibit anti‐inflammatory, antiviral, and glucolipid metabolism‐regulating activities (Jakubczyk et al. 2023; Hu et al. 2021; Xu et al. 2020; Yang et al. 2017; Ziemlewska et al. 2024). Table 1 summarizes the functional properties and health effects associated with each bioactive component.

The interplay between gut microbiota and the gut‐brain axis is critical for understanding diabetes‐associated cognitive impairments (Loh et al. 2024). Current evidence indicates that gut microorganisms profoundly modulate the host nervous system by regulating gastrointestinal function, immune responses, and endocrine signaling (Socała et al. 2021). Notably, microbially derived SCFAs can cross the blood–brain barrier and influence cognitive processes (Dalile et al. 2019). In diabetic individuals, gut dysbiosis often impairs SCFA production, potentially exacerbating cognitive decline via gut‐brain axis dysregulation (Liu, de Bruijn, et al. 2020). Additionally, gut microbiota synthesize neuroactive compounds (e.g., dopamine, serotonin), which regulate emotion and cognition through gut‐brain communication (Ojo et al. 2020). Fermented tea—rich in polyphenols and other bioactive compounds—related cognitive decline by modulating gut microbiota composition and metabolism. Investigating interactions among fermented tea, gut microbiota, and the gut‐brain axis could yield novel therapeutic strategies for diabetic cognitive impairment and deepen understanding of gut‐brain axis dynamics (Xia et al. 2019; Zhang, Zhang, et al. 2021). Thus, fermented tea represents a promising nutraceutical modulator of the microbiota‐gut‐brain axis, warranting targeted investigation into its capacity to restore microbial SCFA production, neuroactive metabolite synthesis, and gut‐brain signaling integrity in diabetic cognitive pathology.

The gut‐brain axis constitutes a bidirectional neuroendocrine network linking the gastrointestinal tract and central nervous system (Socała et al. 2021). Its regulatory significance in diabetic cognitive impairment pathogenesis and management is increasingly recognized (Loh et al. 2024). Diabetes‐related cognitive decline involves multifactorial mechanisms, with gut‐brain axis disruption identified as a key contributor (MahmoudianDehkordi et al. 2018). Alterations in microbial composition may affect cognition through diverse metabolic pathways.

Gut‐brain axis signaling operates via neural, immune, and endocrine routes (Zhang et al. 2022; Momen et al. 2024). Key metabolites including SCFAs function as vital signaling molecules that enhance intestinal barrier integrity, attenuate inflammation, and improve insulin sensitivity. Moreover, neuromodulators including brain‐derived neurotrophic factor and serotonin further contribute to diabetes‐associated cognitive deficits (Rao 2013; Zhu et al. 2024). These multifaceted signaling pathways present interconnected therapeutic targets for addressing gut‐brain axis dysregulation in diabetic cognitive pathology, with fermented tea‐derived bioactivities offering potential modulation of SCFA production and neuromodulator expression.

Additionally, polyphenols and prebiotics in fermented tea help maintain gut microbial equilibrium and mucosal barrier function, suggesting therapeutic potential against diabetic cognitive decline (Khan and Mukhtar 2018; Chen et al. 2019; Chen and Yang 2020; Zhou et al. 2019). Advanced techniques (e.g., high‐throughput sequencing, metabolomics) are now mapping gut microbiome lineages associated with diabetic cognitive impairment (Xiang et al. 2021; Sun et al. 2023; Gao, Ye, et al. 2022) and elucidating host‐microbe communication pathways. Future studies should clarify molecular mechanisms by which fermented tea modulates the gut‐brain axis, thereby informing innovative strategies to prevent or treat diabetic cognitive dysfunction.

The gut‐brain axis mediates bidirectional communication between the central nervous system and gut microbiota, significantly influencing diabetic cognitive dysfunction progression. Current evidence suggests diabetic gut microbiome alterations may perturb central nervous system function via the gut‐brain axis (Loh et al. 2024; Longo et al. 2023), involving multiple biomolecules and pathways. For instance, microbially produced SCFAs cross the blood–brain barrier to modulate brain activity (Dalile et al. 2019). Diabetes‐related metabolic disturbances (e.g., insulin resistance) may further impair cognition by dysregulating these metabolites (Biessels and Despa 2018; Liu, Dai, et al. 2020; Zhou et al. 2022). This pathophysiological cascade—linking gut dysbiosis, impaired SCFA signaling, and metabolic dysfunction—establishes the gut‐brain axis as a critical therapeutic target, with fermented tea offering potential to concurrently modulate microbial ecology and neuroactive metabolite bioavailability in diabetic cognitive impairment.

Elevated levels of inflammatory markers (e.g., tumor necrosis factor‐α and interleukin‐6) in diabetes can translocate to the brain via circulation, inducing neuroinflammation that disrupts neuronal plasticity and survival, ultimately compromising cognition (Zhang et al. 2023; Lei et al. 2024). Bioactive compounds in fermented tea (e.g., polyphenols, caffeine, amino acids) modulate gut microbiota, suppress inflammation, and preserve neuronal integrity (Jeong et al. 2020; Tang et al. 2019; Pan et al. 2023; Unban et al. 2019), suggesting novel therapeutic avenues for diabetic cognitive decline through the gut‐brain axis (Table 2).

Future studies should employ advanced sequencing technologies to characterize gut microbiome functionality. Integrated multi‐omics approaches—including transcriptomics, metabolomics, and neuroimaging analyses—will advance understanding of gut‐brain axis influences on cognition. Identifying specific biomarkers may further guide clinical interventions.

Research on the gut‐brain axis increasingly impacts fermented tea components in the regulation of gut microbiota. The diversity and balance of the gut microbiome are critical determinants of human health, significantly influencing metabolic and immune functions. Fermented tea contains diverse bioactive compounds, including polyphenols, polysaccharides, amino acids, and alkaloids, which contribute to shaping the intestinal environment and modulating microbial communities. Particularly, catechins and other phenolic constituents in fermented tea promote the proliferation of probiotics while suppressing pathogenic strains, thereby fostering a more favorable gut microbiome profile (Khan and Mukhtar 2018; Tang et al. 2019; Júnior et al. 2022). Furthermore, metabolites derived from fermented tea, including SCFAs, modulate microbial composition and function, enhance intestinal barrier integrity, and mitigate intestinal inflammation through pH regulation (Song et al. 2022; Fan et al. 2013). These molecular interactions extend systemically, potentially influencing cognitive function via circulatory or neurotransmission pathways connecting the gut to the brain (Li, Zhang, et al. 2023). Alterations in gut microecology have been correlated with cognitive impairment in diabetes, as dysbiosis in diabetic patients may disrupt neuroinflammatory pathways through metabolite dysregulation, exacerbating cognitive decline (Lu et al. 2022; Ng et al. 2021). Consequently, interventions including fermented tea consumption may confer therapeutic benefits for diabetic cognitive impairment by indirectly or directly ameliorating gut flora composition. These findings highlight the potential of fermented tea components in mitigating diabetes‐associated cognitive dysfunction through modulation of the gut microbiota.

Evidence suggests that bioactive compounds in fermented tea critically modulate interactions with the gut microbiota (Sun et al. 2021). These compounds not only promote the growth of beneficial bacteria but also inhibit the function of specific pathogenic strains, thereby enhancing intestinal health. Certain gut microbes metabolize polyphenols to produce SCFAs, which regulate intestinal barrier integrity, reduce inflammation, and significantly contribute to gut–brain axis homeostasis (Zhang, Cheng, and Zhang 2021; Xie et al. 2022). Crucially, butyrate and its derivatives regulate G protein‐coupled receptor (GPCR) activity, influencing insulin sensitivity and glucose metabolism; this is a mechanism potentially relevant for interventions targeting diabetes‐related cognitive decline (Mayorga‐Ramos et al. 2022). Moreover, these metabolites can cross the blood–brain barrier to directly influence brain function, eliciting anti‐inflammatory responses within the central nervous system (Stilling et al. 2016). The targeted modulation of gut microbiota by fermented tea bioactives suggests its dietary incorporation represents a non‐pharmacological strategy to influence microbial composition and metabolic output, potentially ameliorating diabetes‐associated cognitive issues. Consequently, elucidating the precise relationships between fermented tea constituents and gut microbiota is essential for advancing understanding of the gut–brain axis in clinical contexts and developing innovative therapeutic approaches for diabetic complications.

Bioactive components in fermented tea, including catechins, polysaccharides, and organic acids, interact with gut microbiota to preserve intestinal mucosal barrier integrity. These compounds promote beneficial probiotics (e.g., Bifidobacterium, Lactobacillus) while inhibiting detrimental bacteria, supporting gut ecosystem equilibrium (Gao, Wang, et al. 2023). By reinforcing the intestinal barrier, fermented tea contributes to the management of diabetic cognitive dysfunction, impacting inflammatory responses vital for gut‐brain axis communication. Studies demonstrate that fermented tea constituents upregulate tight junction protein expression, improve barrier function, and reduce circulating endotoxin and inflammatory markers, thereby conferring neuroprotection and potentially enhancing cognitive capabilities (Jakubczyk et al. 2023; Qin et al. 2010; Prasanth et al. 2019; Mhd Jalil et al. 2019). Understanding this mechanism provides insights for addressing diabetic complications and supports the application of fermented tea in functional foods and pharmaceutical development.

Fermented tea, recognized for its nutritional value, has garnered significant scientific interest for its potential in addressing diabetic cognitive dysfunction. Key active constituents, such as catechins and polyphenols, exert effects on neural signaling pathways (Sun et al. 2021; Uniyal et al. 2021). These pathways enhance cerebral insulin signaling, support neuronal function and plasticity, activate the sympathetic nervous system, and modulate gut microbiota composition, collectively improving nervous system function via the gut‐brain axis (Xu et al. 2021; Zhang, Cheng, and Zhang 2021). Fermented tea components may promote myelination, protect neurons from oxidative stress, and alleviate diabetic neuropathy through anti‐inflammatory mechanisms (Ojo et al. 2020; Sabu et al. 2002). Furthermore, polyphenols and prebiotics regulate the gut milieu, fostering beneficial bacteria growth and indirectly influencing cognition by modulating gut‐derived signaling molecules (e.g., SCFAs). Elucidating these processes clarifies the benefits of fermented tea and reveals novel therapeutic avenues for mitigating cognitive decline in diabetic patients.

Bioactive compounds in fermented tea (e.g., polyphenols, alkaloids) may ameliorate diabetic cognitive dysfunction via gut‐brain axis modulation. These components effectively regulate gut microbiota composition (Van Buiten et al. 2018; Teixeira Oliveira et al. 2023), beneficially impacting intestinal barrier integrity. Enhanced barrier function reduces systemic inflammatory agent dissemination and dampens inflammatory signaling to the brain (Ng et al. 2021; Lee et al. 2023). Antioxidant tea polyphenols synergize with microbially derived SCFAs to modulate immune responses, crucially mitigating gut oxidative stress, a key factor in diabetes‐associated neuroinflammation (Kim et al. 2020, 2021). Fermented tea also supports glycemic control, reduces insulin resistance, and enhances insulin sensitivity, contributing to cognitive function recovery (Lee et al. 2015). These findings underscore fermented tea's significant role in regulating the gut‐brain axis, modulating inflammation, and influencing immune responses in diabetic cognitive impairment, suggesting promising therapeutic strategies for future investigation.

Fermented tea has attracted considerable attention for its potential to mitigate diabetes‐associated cognitive impairment. Analysis of its components and gut‐brain communication pathways reveals that bioactive compounds regulate endocrine function, thereby influencing nervous system activity (Yang et al. 2017; Ma et al. 2022), with positive implications for cognition. For instance, polyphenols enhance insulin sensitivity in diabetic patients, improving metabolic health and cognitive performance (Li et al. 2022; Sabu et al. 2002; Miyata et al. 2013). Moreover, microbially produced SCFAs (derived from amino acid and polysaccharide fermentation) cross the blood–brain barrier to influence the central nervous system, regulating neural pathways involved in learning and memory. Fermented tea also contains bioactives affecting neurotransmitter production and release, significantly contributing to synaptic transmission and cognitive maintenance (Pavlović et al. 2023), as shown as Figure 1. Critically, the efficacy of fermented tea likely arises from the synergistic action of multiple bioactive compounds, not a single constituent (Tang et al. 2019). Therefore, further research is required to establish dose–response relationships and identify optimal bioactive combinations for clinical applications. Developing novel interventions for diabetic cognitive decline necessitates thorough investigation of fermented tea component interactions along the gut‐brain axis to facilitate improved therapeutic strategies.