The gut-brain axis facilitates bidirectional communication between the gut microbiota and the CNS through neural, endocrine, and immune pathways (Forsythe and Kunze, 2013).

Microbial metabolites, particularly SCFAs like acetate, propionate, and butyrate, are produced through the fermentation of dietary fibers by gut bacteria (Abdelhalim, 2024). SCFAs have significant effects on host metabolism and brain function (Qian et al., 2022). Butyrate, for instance, has anti-inflammatory properties and can enhance insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibiting histone deacetylases (HDACs), which regulate gene expression involved in glucose and lipid metabolism (Matheus et al., 2017).

Butyrate also promotes neurogenesis and protects against neuroinflammation by inhibiting nuclear factor-kappa B (NF-κB) signaling, a key pathway in inflammatory responses (Alpino et al., 2024). This neuroprotective effect is crucial in maintaining cognitive function and preventing neurodegenerative diseases. Additionally, SCFAs can influence gut-brain signaling through the gut hormone system, including the release of peptides like glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), which regulate appetite and glucose homeostasis (Lai et al., 2024).

Dysbiosis, characterized by a reduced diversity and altered composition of gut microbiota, has been strongly associated with the development of insulin resistance (Abildinova et al., 2024). For example, a study demonstrated that individuals with type 2 diabetes had significantly lower levels of Firmicutes and increased Bacteroidetes, suggesting a microbial imbalance linked to insulin resistance (Craciun et al., 2022). Another study identified specific gut microbial markers associated with insulin resistance and type 2 diabetes, further supporting the link between dysbiosis and metabolic dysfunction (Wu et al., 2023). One primary mechanism involves increased intestinal permeability, often referred to as “leaky gut” (Vanuytsel et al., 2021). Dysbiosis can disrupt the gut barrier function, allowing the translocation of lipopolysaccharides (LPS) from gram-negative bacteria into the bloodstream, leading to metabolic endotoxemia (Violi et al., 2023). This endotoxemia triggers systemic inflammation, which impairs insulin signaling and promotes insulin resistance (Huang et al., 2021; Figure 1).

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) play a crucial role in this process by activating serine kinases that phosphorylate insulin receptor substrates, thereby inhibiting their ability to transmit insulin signals (Amabebe et al., 2020). In addition to TNF-α and IL-6, other pro-inflammatory cytokines such as interleukin-1β (IL-1β) also contribute to insulin resistance by exacerbating inflammatory pathways (Al-Mansoori et al., 2022). These cytokines interact in a complex network, amplifying each other’s effects through feedback loops that further promote inflammation (Megha et al., 2021). For instance, TNF-α can induce the production of IL-6 and IL-1β, which in turn perpetuate inflammation by activating downstream signaling pathways such as nuclear factor-kappa B (NF-κB) (Brasier, 2010). This persistent inflammatory state not only disrupts insulin signaling but also contributes to systemic metabolic dysfunction, highlighting the intricate and multifaceted role of cytokines in insulin resistance (Rehman and Akash, 2016). Moreover, dysbiosis-induced alterations in bile acid metabolism can influence insulin sensitivity (Patra et al., 2023). Bile acids act as signaling molecules that modulate metabolic processes through their receptors, such as farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5) (de Aguiar Vallim et al., 2013). Dysbiosis can disrupt bile acid homeostasis, leading to impaired insulin signaling and glucose metabolism.

Gut microbiota influence glucose metabolism through various pathways, including the regulation of gluconeogenesis and glycolysis in the liver (Utzschneider et al., 2016). Certain gut bacteria, such as Akkermansia muciniphila, have been shown to improve glucose tolerance and insulin sensitivity by modulating mucin production and enhancing gut barrier integrity (Xu et al., 2020). Additionally, gut microbiota can affect the expression of glucose transporters in the intestinal epithelium, influencing glucose absorption and utilization (Ridaura et al., 2013).

Studies have demonstrated that FMT from lean donors to individuals with metabolic syndrome can improve insulin sensitivity, highlighting the potential of gut microbiota manipulation as a therapeutic strategy for insulin resistance (Kootte et al., 2017). Furthermore, dietary interventions that promote beneficial gut bacteria, such as high-fiber diets, have been shown to improve glycemic control and reduce the risk of type 2 diabetes (Deehan and Walter, 2016).

Insulin plays a crucial role in brain function, influencing synaptic plasticity, neurotransmitter release, and neuronal survival (Kleinridders et al., 2014). Insulin signaling in the brain is mediated through the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R), which activate downstream pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) (Ferreira et al., 2018). These pathways are essential for maintaining cognitive functions, including learning and memory.

Impaired insulin signaling in the brain, often referred to as brain insulin resistance, has been associated with cognitive decline and neurodegenerative diseases like Alzheimer’s disease (Escobar et al., 2022). Brain insulin resistance leads to decreased glucose uptake and utilization, increased oxidative stress, and neuroinflammation, all of which contribute to synaptic dysfunction and neuronal loss (Arnold et al., 2018).

Insulin resistance is linked to cognitive impairment through several mechanisms (Tyagi and Pugazhenthi, 2021). Hyperinsulinemia, a compensatory response to peripheral insulin resistance, can lead to reduced insulin transport across the blood–brain barrier, resulting in decreased insulin availability in the brain (Vogelsang et al., 2018). This deficiency impairs glucose metabolism and energy production in neurons, contributing to cognitive deficits.

Additionally, insulin resistance is associated with increased amyloid-beta (Aβ) production and decreased clearance, a hallmark of Alzheimer’s disease pathology (Escobar et al., 2022). Insulin can modulate the activity of enzymes involved in Aβ production and degradation, and impaired insulin signaling exacerbates Aβ accumulation and neurotoxicity. Moreover, insulin resistance is linked to tau hyperphosphorylation, another key feature of Alzheimer’s disease, through the dysregulation of glycogen synthase kinase-3β (GSK-3β) (Rodriguez-Rodriguez et al., 2017).

SCFAs produced by gut microbiota have been shown to influence cognitive function through multiple pathways (Qian et al., 2022). SCFAs, such as acetate, propionate, and butyrate, exert their influence on cognitive function through several mechanisms (Qian et al., 2022). These include modulating the production of neurotransmitters like serotonin, gamma-aminobutyric acid (GABA), and dopamine, which are crucial for mood regulation and cognitive processes (Gasmi et al., 2022). SCFAs stimulate the release of gut hormones, such as glucagon-like peptide-1 (GLP-1), which can cross the blood–brain barrier and affect neuronal signaling (Moțățăianu et al., 2023). Additionally, butyrate has been shown to inhibit histone deacetylase, enhancing gene expression linked to neuroprotection and cognitive health (Jaworska et al., 2017). Butyrate, in particular, enhances synaptic plasticity and memory formation by increasing the expression of brain-derived neurotrophic factor (BDNF) and promoting histone acetylation, which facilitates gene transcription involved in neurogenesis (Li et al., 2022). Butyrate also has anti-inflammatory properties, reducing neuroinflammation and protecting against cognitive decline (Matt et al., 2018; Figure 2).

SCFAs can also modulate the gut-brain axis by influencing the production of gut hormones such as GLP-1 and PYY, which have neuroprotective effects and regulate appetite and energy homeostasis, as previously described (Lai et al., 2024). Furthermore, SCFAs can cross the blood–brain barrier and directly impact brain function by interacting with G-protein-coupled receptors (GPCRs) expressed in the CNS (Frost et al., 2014).

In addition to SCFAs, other microbial metabolites such as tryptophan metabolites, bile acids, and neurotransmitters play significant roles in cognitive function (Figure 3). Tryptophan metabolites, including indole and its derivatives, can modulate the gut-brain axis by interacting with the aryl hydrocarbon receptor (AhR) and influencing immune responses and neuroinflammation (O'Mahony et al., 2015). Alterations in tryptophan metabolism have been linked to depression and cognitive impairment, highlighting the importance of gut microbiota in mental health.

Bile acids, traditionally known for their role in digestion, also function as signaling molecules that can influence brain function. Altered bile acid metabolism has been associated with cognitive decline and neurodegenerative diseases (Baloni et al., 2020). Bile acids can activate TGR5 and FXR receptors in the brain, regulating inflammation and synaptic plasticity (de Aguiar Vallim et al., 2013).

Neurotransmitters produced by gut microbiota, such as gamma-aminobutyric acid (GABA) and serotonin, also significantly impact cognitive function. GABA, an inhibitory neurotransmitter, can help regulate mood and anxiety levels, while serotonin is crucial for mood stabilization and is linked to various cognitive processes. The communication between gut-derived neurotransmitters and the central nervous system may occur through multiple pathways, including direct neural connections and the bloodstream. Recent studies suggest that dysregulation of these neurotransmitter levels can be associated with mood disorders and cognitive impairments, further emphasizing the intricate relationship between gut microbiota and mental health.

Probiotics, live microorganisms that confer health benefits to the host, have shown promise in improving insulin sensitivity and cognitive function. Specific strains of probiotics, such as Lactobacillus and Bifidobacterium, have been shown to reduce inflammation, enhance gut barrier integrity, and modulate metabolic pathways (Wallace and Milev, 2017). Probiotic supplementation can improve glycemic control and reduce markers of insulin resistance in individuals with metabolic disorders (Kootte et al., 2017; Salles et al., 2020).

Prebiotics, nondigestible dietary fibers that promote the growth of beneficial gut bacteria, also have significant potential in modulating the gut-brain-metabolic axis. Prebiotics such as inulin and fructooligosaccharides (FOS) can increase SCFA production, improve gut barrier function, and reduce systemic inflammation (Bindels et al., 2015; Costa et al., 2022). Dietary interventions that incorporate prebiotics can enhance insulin sensitivity and cognitive function by promoting a healthy gut microbiota composition (Deehan and Walter, 2016; Zhang et al., 2019).

Diet plays a crucial role in shaping the gut microbiota and influencing the gut-brain axis. High-fiber diets, rich in fruits, vegetables, and whole grains, promote the growth of beneficial gut bacteria and increase SCFA production, which can improve metabolic and cognitive health (Patterson et al., 2016). Conversely, diets high in saturated fats and refined sugars can lead to dysbiosis, increased intestinal permeability, and systemic inflammation, contributing to insulin resistance and cognitive decline (Olson et al., 2018; Baspakova et al., 2024).

Intermittent fasting (IF) has emerged as a dietary intervention with potential benefits for the gut-brain-metabolic axis. IF involves cycles of eating and fasting, which can enhance gut microbiota diversity, reduce inflammation, and improve insulin sensitivity (Mattson et al., 2014; Guzzetta et al., 2022). IF has also been shown to promote neurogenesis and protect against cognitive decline by activating adaptive stress response pathways and increasing BDNF levels (Mattson et al., 2014).

FMT involves the transfer of gut microbiota from a healthy donor to a recipient with dysbiosis. FMT has shown promise in treating metabolic disorders and improving insulin sensitivity by restoring a healthy gut microbiota composition (Kootte et al., 2017). Emerging evidence suggests that FMT can also improve cognitive function in individuals with neurodegenerative diseases such as Alzheimer’s disease (Baunwall et al., 2020; Tixier et al., 2022).

The therapeutic potential of FMT lies in its ability to reestablish a balanced gut microbiota, reduce systemic inflammation, and enhance gut barrier integrity. However, further research is needed to understand the long-term effects and optimize the protocols for FMT in treating metabolic and cognitive disorders (Baunwall et al., 2020; Tixier et al., 2022).

This comprehensive review aims to address the aforementioned deficiencies by providing a detailed analysis of the current understanding of the gut-brain-metabolic axis and its implications for insulin resistance and cognitive function. By synthesizing the latest research from various disciplines, including microbiology, neuroscience, and metabolic health, this review was offered a holistic perspective on the complex interplay between the gut microbiota, insulin resistance, and cognitive processes.

The findings of this review will be instrumental in guiding future research directions and informing the development of novel therapeutic interventions. For instance, future studies could explore the potential of targeting specific gut microbial species or their metabolites to improve insulin sensitivity and cognitive function. Additionally, research could focus on designing clinical trials that assess the efficacy of dietary modifications or probiotics in enhancing cognitive health in individuals with insulin resistance. By elucidating these pathways, we aim to pave the way for targeted interventions that leverage the gut-brain axis to mitigate cognitive decline. By elucidating the specific mechanisms underlying the gut-brain-metabolic axis, researchers and clinicians can work toward personalized approaches to prevent and treat metabolic and neurodegenerative disorders, ultimately improving the quality of life for affected individuals.

Therapeutic interventions such as probiotics, prebiotics, dietary modifications, and FMT offer promising avenues for modulating the gut-brain-metabolic axis. Probiotics have been shown to increase the production of SCFAs, such as butyrate, which improve gut barrier integrity, reduce neuroinflammation, and enhance insulin sensitivity. SCFAs also cross the blood–brain barrier, impacting neurotransmitter synthesis and modulating cognitive function. Prebiotics selectively stimulate the growth of beneficial bacteria, thereby influencing metabolic pathways related to glucose homeostasis and neuroprotection. FMT, by restoring a balanced microbiota, can reduce systemic inflammation, restore insulin signaling, and improve cognitive performance by promoting the production of neuroactive metabolites. The efficacy of these interventions in improving insulin sensitivity and cognitive function underscores the potential for personalized approaches to prevent and treat metabolic and neurodegenerative diseases (Kootte et al., 2017; Matt et al., 2018). However, further research is needed to optimize these interventions, understand their long-term effects, and identify the most effective strategies for different populations.

While therapeutic interventions targeting the gut-brain-metabolic axis, such as probiotics, prebiotics, dietary modifications, and FMT (Contarino et al., 2023), show promise in regulating insulin resistance and cognitive function, several limitations and unresolved issues warrant attention:

Despite the promising findings regarding the role of gut microbiota in regulating insulin resistance and cognitive function, several challenges and controversies remain in this field:

Future research should focus on elucidating the specific microbial species and metabolites involved in modulating insulin resistance and cognitive function. To achieve this goal, researchers could employ high-throughput sequencing techniques to identify and characterize gut microbiota in diverse populations, particularly those with varying degrees of insulin resistance and cognitive impairment. Additionally, metabolomic analyses can be utilized to profile metabolites produced by these microbial communities. Integrating these approaches with clinical studies will allow for the exploration of causal relationships and the identification of potential biomarkers for early intervention. Understanding these specific interactions will be crucial for developing targeted therapies aimed at improving metabolic and cognitive health.

Advances in metagenomics, metabolomics, and bioinformatics will enable a deeper understanding of the complex interactions within the gut microbiota and their impact on host health (Zhang Q. et al., 2022; Takeuchi et al., 2023). Additionally, exploring the role of the gut-brain-metabolic axis in various disease states, including neurodegenerative diseases, psychiatric disorders, and metabolic syndromes, will provide valuable insights into the underlying mechanisms and potential therapeutic targets (Ridaura et al., 2013; Kootte et al., 2017).

Moreover, the long-term effects and safety of therapeutic interventions targeting the gut-brain-metabolic axis, such as probiotics, prebiotics, and FMT, are not well-established. Longitudinal studies are necessary to evaluate the sustainability and potential adverse effects of these interventions (Fekete et al., 2024; Makris et al., 2021).

The gut-brain-metabolic axis represents a promising area of research with significant implications for understanding and treating metabolic and cognitive disorders. Emerging evidence suggests that targeting the gut microbiota through dietary interventions, probiotics, prebiotics, and FMT can improve insulin sensitivity and cognitive function, offering new avenues for therapeutic strategies.

Future research should focus on identifying the specific microbial species and metabolites that play critical roles in modulating the gut-brain axis and their impact on metabolic and cognitive health. Advances in sequencing technologies and bioinformatics will enable a more comprehensive understanding of the gut microbiota and its interactions with the host.

Additionally, personalized approaches that consider individual variations in gut microbiota composition, genetics, and lifestyle factors will be crucial for optimizing therapeutic interventions. Understanding the long-term effects and safety of these interventions, particularly FMT, will be essential for their clinical application (Kootte et al., 2017; Mattson et al., 2014).

Exploring the role of the gut-brain-metabolic axis in various disease states, including neurodegenerative diseases, psychiatric disorders, and metabolic syndromes, will provide valuable insights into the underlying mechanisms and potential therapeutic targets. Ultimately, a better understanding of the gut-brain-metabolic axis will pave the way for novel strategies to promote metabolic and cognitive health, improving the quality of life for individuals affected by these interconnected disorders (Arnold et al., 2018).