The gut microbiota‐astrocyte axis: Implications for type 2 diabetic cognitive dysfunction

Abstract Background Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self‐monitoring of blood glucose and the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta‐amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes‐related complications. Gut microbes and their metabolites can drive astrocyte activation. Aims We reviewed the pathological progress of DCD related to the “gut microbiota‐astrocyte” axis in terms of peripheral and central inflammation, intestinal and blood–brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets. Conclusion “Gut microbiota‐astrocyte” axis, unique bidirectional crosstalk in the brain‐gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.


| INTRODUC TI ON
Diabetic cognitive dysfunction (DCD) refers to the impairment of cognitive functions such as language and visual memory, information processing speed, and executive functions caused by diabetes mellitus. The 2021 American Diabetes Association (ADA) guidelines have explicitly identified diabetic cognitive impairment as a common complication of type 2 diabetes mellitus (T2DM) and indicate that the severity of cognitive impairment can deteriorate significantly over time. 1 As population aging trends and the prevalence of diabetes continue to increase, the number of potential patients with DCD will continue to increase. The Rotterdam study found that patients with T2DM had about twice the risk of developing dementia as normal individuals, with a relative risk of 1.9, and the 95% confidence interval was 1.3-2.8. 2 Many epidemiological studies have shown a close relationship between diabetes mellitus and cognitive impairment. 3,4 A systematic review and meta-analysis of 144 prospective studies demonstrated that diabetes conferred a 1.25-to 1.91-fold excess risk for cognitive disorders. High 2-h postload glucose, glycosylated hemoglobin (HbA1c), and fasting plasma insulin levels were associated with an increased risk of dementia. 5 In addition, studies suggest that mild cognitive impairment in diabetes exists in all age groups. 6,7 Cognitive development in adolescents 8 and neurodegenerativity 9,10 in older adults show mild changes compared with controls, suggesting that the burden of cognitive dysfunction is also present in young patients.
Type 2 diabetes mellitus and Alzheimer's disease (AD) have significant overlap in risk factors and pathophysiological mechanisms. However, neuropathology studies from multiple cohort studies have suggested no association between DCD and the characteristic pathological β-amyloid (Aβ) deposits or neurofibrillary tangle of AD. 11,12 Systemic alterations in T2DM are associated with pathophysiological mechanisms that lead to impairment of cognitive function. 13,14 Peripheral insulin resistance (IR) is thought to directly induce brain IR, and insulin signaling exerts a variety of effects in the brain regulating synaptic plasticity and peripheral energy metabolism. 15 IR in specific brain regions was associated with decreased function of the posterior cingulate cortex and right middle temporal gyrus. 16 Chronic hyperglycemia can induce chronic low-grade inflammation by the accumulation of advanced glycation end products (AGEs). Nerve cell oxidative stress and inflammation are also important causes of neurodegeneration and lead to neuronal mitochondrial dysfunction.
Neurons rely on the intact mitochondrial function to synthesize and secrete neurotransmitters, enhance synaptic plasticity, and maintain membrane potential. It should be noted that disorders of glucose and lipid metabolism, IR, mitochondrial dysfunction, and chronic inflammatory states are integral pathological links that together lead to endothelial damage in the cerebral microcirculation 17,18 and neurodegeneration. 19 Prior neuroimaging studies have shown that specific functional and structural brain changes in patients with DCD are associated with cognitive impairment. 20 T2DM accelerates the reduction of total brain volume in elderly patients. 21 In multiple cohort studies and meta-analyzes, differences in brain volumes related to diabetes emerge in young adulthood and increase with T2DM duration. 22,23 In the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study, T2DM was associated with decreased global brain volume and decreased uptake of 18F-fludeoxyglucose (18F-FDG) in the frontal lobe, sensorimotor cortex, and striatum. 24 In a cohort study of 713 patients with magnetic resonance imaging (MRI) and cognitive testing, T2DM-related gray matter loss was thought to be primarily distributed in the medial temporal lobe, anterior cingulate gyrus, and medial prefrontal lobe. The white matter loss is mainly in the frontal and temporal lobes and is associated with poor visuospatial working memory (VSWM), planning capacity, and processing speed. 25 Reduced brain volume in T2DM is associated with complex factors, including loss of neuroglia and axons, thinning and atrophy of white matter, arteriosclerosis, and venous collagen degeneration. 20 Diffusion tensor imaging (DTI) studies have found the presence of microstructural lesions linked to white matter tissue and neural functional networks in T2DM. 26 Decreased information processing speed in T2DM patients is associated with decreased measures of overall brain connection. 27,28 In addition, studies have shown that resting-state functional connectivity is reduced in the default mode network and is strongly associated with HOMA-IR. 29 The studies of neural function networks promote the exploration of the cooperative changes among multiple functional brain areas of T2DM and further explain the effect of DCD on higher mental function.
In recent years, expert consensus and professional guidelines have called for the strengthening of early screening for DCD 30,31 and the promotion of common standardized management of cognitive impairment and glycemic control in patients with the disease, 32 to avoid mild cognitive impairment to the deterioration of dementia.
However, there is currently no evidence to support that intensive glucose control and specific Anti-diabetic medication can prevent the progression of cognitive impairment. 33 Emergent research directions in the gut-brain axis as a pathological and therapeutic target of cognitive dysfunctions. 34 Gut microbiota and astrocyte act as sensitive metabolic sensors in gut-brain interactions. The gut microbiota is also an important upstream factor in the activation of astrocytes, which in turn promotes neuroinflammation and neurodegenerative. 35 Large-scale proteomic studies have shown that astrocyte activation and high expression of glycolytic proteins in the brain tissue of patients with dementia may serve as an important pathological marker of early decline in brain energy metabolism and neuroinflammation. 36 In this review, we focus on gut microbiota and astrocyte along the gut-brain axis and attempts to elucidate the specific course of complications associated with impaired neurocognitive function secondary to peripheral metabolic disorders in T2DM.

| A S TRO C Y TE PL A S TI CIT Y MAINTAIN S ME TABOLIS M AND HOMEOS TA S IS IN THE B R AIN
Astrocytes are the most abundant neuroglia in the brain and play important roles in maintaining brain energy metabolism, modulating cerebral blood flow, and regulating neuronal circuits. The role of astrocytes in neurocognitive function has also received considerable attention in recent years. 37 The astrocytes are connected through a gap junction-coupled network and its endfeet ensheath blood vessels as well as neuronal synapses. About 60% of the axon-dendritic synapses in the hippocampus are enveloped by astrocytic processes, forming a tripartite synapse. The astrocyte endfeet connects microvessels to the neurons composing the neurovascular unit and can release vasoactive molecules, thus regulating the cerebral blood flow and BBB permeability. Horng et al. 38 demonstrated that astrocytes in response to inflammatory signals, thus inducing tight junction (TJ) formation, limiting the number of activated T cells infiltrating the CNS.
The astrocyte, which serves as the main CNS glycogen storage cell, is coupled to the oxidative phosphorylation system (OXPHOS) metabolism of neurons through aerobic glycolysis. 39 The astrocyte mediates the expansion of regional cerebral arteries in response to synaptic energy demands, matching blood flow to neuronal activity. 40,41 Astrocytes transfer glucose from the perivascular to the synapse to support the energy needs of neurons via glucose transporter 1 (GLUT1) and the endoplasmic reticulum pathway mediated by G6Paseβ, G6PT, and G6Paseβ. 42 Under conditions of high energy demands such as glucose deprivation or intense nerve activity, and with limited energy availability such as hypoglycemia, astrocyte aerobic glycolysis can rapidly deliver pyruvate and lactic acid to maintain brain energy metabolism homeostasis. 43 The high glycolytic activity of astrocytes results in a significant increase in the flux of the pentose-phosphate pathway (PPP) to produce NADPH and glutathione, thus resisting neuronal oxidative stress. 44 Astrocyte to neuron's nutritional and energetic support is essential for long-term memory formation. 45 The astrocyte regulates brain neuroplasticity and neurogenesis by releasing glial transmitters such as brain-derived neurotrophic factor (BDNF) and astrocytederived neurotrophic factor (ADNF). 45 Astrocytes regulate synaptic plasticity via metabolic pathways with neurons, such as the glutamine-glutamate cycle 46,47 and the astrocyte-neuron lactate shuttle (ANLS), 48,49 thereby affecting memory formation. To maintain neural circuit homeostasis and thus support cognitive function, astrocytes eliminate unnecessary excitatory synaptic connections. 50 The astrocyte also works on neural network projections. Kol et al. 51 demonstrated that astrocytes could modulate hippocampal-cortical communication in the anterior cingulate cortex during learning, thereby promoting the formation of remote memory.
Reactive astrocytes contribute to cognitive decline and metabolic homeostasis disorders. 27 Astrocyte proliferation and high expression of the activation marker protein glial fibrillary acidic protein (GFAP) are hallmarks of neuroinflammation that arise with the neurodegenerative state. Astrocyte activation has been observed in various animal models of diabetes (Table 1). Zhang et al. 52 have demonstrated that a high-fat diet (HFD) induces upregulation of astrocyte IκK/NF-κB, which in turn impairs astrocytic processes' plasticity. The astrocyte led to changes in extracellular GABA and BDNF in the hypothalamus, thus contributing to weight gain and impaired glucose tolerance. García-Cáceres et al. 53 showed that hypothalamic astrocytes regulate glucose uptake rate at the BBB by modulating insulin signaling/GLUT1, which co-controls brain glucose sensing and systemic glucose metabolism. The potential immunometabolic mechanism makes the astrocyte activation accompanied by its metabolic plasticity damage, which leads to the attenuation of brain energy metabolism and its adaptive changes. Rahma et al. 54 showed that the hypothalamic neuroinflammatory response in T2DM is associated with the metabolic shift from glycolysis to OXPHOS. Specific inhibition of astrocyte pyruvate dehydrogenase kinase (PDK)-2 reduces hypothalamic inflammation and lactate levels, reversing the diabetes-induced increase in food intake.

| INTE S TINAL DYS BAC TERI OS IS IS A COMMON PATHOLOG IC AL FE ATURE OF T2DM AND COG NITIVE DYS FUN C TI ON
The interplay between gut microbiota and host metabolism predisposes to drive T2DM pathogenesis through gut permeability change, chronic metabolic inflammation, IR, and metabolic energy disorder. The commonly reported results are that the genera of Bifidobacterium, Bacteroides, Faecalibacterium, Akkermansia, and Roseburia have a potential role in preventing T2DM, whereas Ruminococcus, Fusobacteria, and Blautia genera are associated with T2DM pathogenesis. 68 A microbiome research of 123 nonobese and 169 obese Danish subjects showed that individuals with low gut microbiota abundance were more likely to be obese, IR and dyslipidemia, and the inflammatory phenotype is more pronounced. 69 A cross-sectional analysis of prospective cohorts from the Rotterdam study and Life Lines-DEEP suggests that higher microbial α-diversity and more butyrate (NaB)-producing bacteria are associated with lower T2DM incidence and lower levels of IR. 70 Microbial balance is essential for maintaining metabolic homeostasis and protecting cognitive function. 71 Restoring intestinal flora balance can alleviate cognitive impairment and neuropsychiatric symptoms. A cross-sectional study of microbiome data from 597 young Cardia patients examined the association between β-diversity of the gut microbiota and multiple cognitive test results. 72 A recent clinical study found a decrease in the abundance of Bifidobacterium and unnamed bacteria RF39 and an increase in the abundance of Peptidococcus and Leucococcus in patients with DCD. The gut microbiota regulates calcium signaling and renin-angiotensin system in relation to DCD. 73 Given the wide variation in gut bacterial dysregulation in DCD, further studies are required to elucidate the underlying mechanisms, and restoration of gut microbiota would be a promising therapeutic avenue for DCD.

| G UT MI CROB I OTA AND ITS ME TABOLIC PRODUC TS TARG E T A S TRO C Y TE S
Intestinal microflora regulates the development and function of astrocytes through neural, endocrine, and immune pathways. The gut microbiota is regulated by genetic and environmental factors, referred to as the second brain, and is also an important shaper of the intestinal microenvironment. Microbial metabolites are important information mediators of the dialogue between gut and brain, most of which can cross the BBB and act directly on the neural microenvironment, and also drive the activation of peripheral immune cells and resident neuroglia of the brain. 74 By expressing pattern recognition receptor receptors (PRRs), such as toll-like receptors (TLRs) and nod-like receptors (NLRs), astrocyte constantly detects microbialassociated molecular patterns (MAMPs) in the neural microenvironment in response to gut bacteria-derived stimuli and initiate innate immune responses. 75 complex class II antigens and costimulatory molecules that activate T cell, thus exacerbating neuroinflammation. 77 Short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and aryl hydrocarbon receptors (AhR) ligands are significantly related metabolites of T2DM, and also have the potential to activate astrocytes ( Figure 1).

| Short-chain fatty acids
Short-chain fatty acids generated by colonic digestion and fermentation of dietary fiber have several roles within in gut microbiota-astrocyte axis, including maintaining energy and glucose homeostasis, relieving inflammation of CNS, and regulating the secretion of neurotransmitters to ameliorate neurodegeneration. SCFAs regulate central satiety and insulin secretion through AMPK signaling, GPCR-dependent pathway, and histone deacetylase inhibition, and influence immune cells and neuroglia to exert beneficial metabolic modulation. 78 The regulation of short-chain fatty acid on astrocytes is gender-related. 79

| Trimethylamine N-oxide
Trimethylamine N-oxide is an influential mediator of gut-brain metabolic interaction. Multiple evidence supports TMAO as a common risk factor for cognitive function 86,87 and metabolic syndrome. 88 The nutrients such as l-choline, carnitine, and betaine in the high- F I G U R E 1 Gut microbiota metabolites drive astrocyte phenotypes. Trimethylamine N-oxide could increase the number of reactive astrocytes and change the marker of reactive activated LCN2 and CD44 protein through the Smuef2/ALK5 axis. Improvement of short-chain fatty acids ratio inhibited astrocytic activation and proinflammatory phenotype. The expression of PGC1α and brain-derived neurotrophic factor in female mice was increased by HDACi, while the function of astrocyte mitochondria and ANLS were improved by butyrate (NaB). A significant correlation between acetate and aryl hydrocarbon receptors (AhR) and GFAP expression was observed in male mice, and the BBB structure was improved. Propionate promotes higher glycolysis and mitochondrial respiration in astrocytes and increases IL-22 expression in male mice. AhR promotes the production of TGFα and VEGF-B by microglia to indirectly regulate the transcriptional program of astrocytes.
In combination with tryptophan-derived metabolites, IFN-I signaling activates in astrocytes and inhibits neuroinflammation.

| Aryl hydrocarbon receptors ligands
The microbial metabolism of dietary tryptophan can be decomposed into various biologically active molecules that bind directly to AhR as hydrocarbon receptor ligands. Through the gut microbiota, tryptophan metabolites may also affect CNS inflammation and contribute to neuropsychiatric disorders. As diabetes severity increases in the PREDIMED cohort, plasma tryptophan levels are likely to rise first and then deplete. 97 The AhR pathway promotes

| G UT MI CROB I OTA-A S TRO C Y TE A XIS CONNEC TS T2DM WITH COG NITIVE DYS FUN C TION
Diabetes-related cognitive impairment is secondary to metabolic disturbances via the gut-brain axis. Gut microbiota disturbance is the key link of metabolic inflammation, immune barrier damage, and energy metabolism. The astrocyte is an important regulator of the immune and metabolic balance of the brain. Gut microbiota, which drives astrocyte activation via neuroimmune pathways, is a target for the treatment and diagnosis of cognitive impairment in diabetes ( Figure 2).

F I G U R E 2
The "gut microbiotaastrocyte" axis is coupled to the pathogenesis of cognitive dysfunction secondary to type 2 diabetes mellitus. Gut microbes and astrocytes are critical factors in the gut-brain axis, leading to diabetic cognitive dysfunction through peripheral and central inflammation, gut and blood-brain barriers, and systemic and brain energy metabolism. Gut microbiota and its metabolites as upstream drivers of astrocytic activation. The reactive astrocytes' morphology and function changes result in blood-brain barrier injury, neuroinflammation, and brain energy metabolic disorder.
in cognitively impaired T2DM patients. 105 Besides these peripheral markers of inflammation, CNS inflammation is also present in obese and T2DM patients, which manifests as neural immune cell infiltration, microglia, and astrocyte activation.
Astrocyte activation is a significant feature of neuroinflammation. Activated astrocyte gene expression switches to a proinflammatory and cytotoxic state, producing a variety of proinflammatory molecules, including cytokines, chemokines, complement factors, and ROS. 97 The synthesis of LacCer in astrocytes promotes CNSinfiltrating monocytes and microglia. 106 The metabesity factor HMG20A is increased under mild inflammation induced by obesity and IR, inducing reactive astrocyte hyperplasia, protecting neurons from metabolic stress, and re-establishing glucose homeostasis. 107 Regulating COX-mediated oxylipin synthesis in astrocytes as a novel potential target in the treatment of hyperglycemia-associated brain injury. 108 The Proinflammatory cytokine produced by dysbacteriosis is an important immune signal that directly activates astrocytes. The

| Gut microbiota and astrocyte are critical hubs to the intestinal and blood-brain barrier
The TJs of the BBB are similar to those of the intestinal immune barrier, including Claudin-5, occulin, and ZO-1. An energetically favorable change in the gut barrier and BBB is an important pathway for interaction between the gut-brain axis. The results showed that BBB dysfunction preceded early biomarkers of cognitive decline other than the accumulation of amyloid and tau proteins. 116 Increased BBB permeability is one of the key pathologies of cognitive impairment in diabetes. 117,118 The accumulation of lipid peroxidation by-products, advanced glycation end products, and mitochondrial superoxide production in diabetes mellitus, causing neovascularization abnormalities and increased capillary density in the CNS.
Blood-brain barrier damage varies in different types of diabetic animals. Increased BBB permeability in more than 84% of brain regions was found in BBZDR/WOR rats, whereas no significant changes were observed in the cerebellum and midbrain. 119 In STZinduced diabetic rats, BBB permeability to small molecules gradually increased over a 28 to 90-day period, and these changes were mainly observed in the midbrain, basal ganglia, cortex, and hippocampal regions. 120 In the HFD diet-induced model of obese T2DM rats, BBB damage predates cognitive impairment and occurs predominantly in the hypothalamus and hippocampus, and continues to deteriorate with the course of the disease. 121 High-fat and high-fructose (HFHF) diet-induced prediabetes mice experienced significant cognitive deterioration, accompanied by the permeability of the BBB and enhanced neuroinflammation in the cortex and hippocampus. 56 Astrocyte is required for the maintenance of BBB integrity in the adult brain, and BBB regulators secreted by other cell types are insufficient to compensate for the loss of astrocyte. 122 In addition to its role in vascularization, astrocytes exert synergic action with endothelial cells via paracrine and extracellular vesicle pathways to regulate TJ protein expression to control BBB integrity. 123 For instance, astrocyte-derived Wnt maintains the activity of Wnt/βcatenin, thereby controlling Cav-1 expression, vesicle abundance, and terminal integrity of the foot in NVU cells. 124 During sustained inflammation, microglia phagocytose astrocytic endfeet and impair BBB function. 125 Impaired BBB is accompanied by elevated GFAP and serves as a biomarker of cognitive impairment in diabetes. 126 The co-culture system of astrocyte and cerebral microvascular opening of the TJ between endothelial cells were strongly inhibited by the anti-HMGB1 monoclonal antibody. 132 The induction of astrocyte proliferation and activation by LPS promotes high expression of proinflammatory and cytotoxic genes, which may be related to BBB destruction. 133

| The gut microbiota-astrocyte axis couples systemic and brain energy metabolism disorders
The brain uses glucose as its primary energy substrate, consuming 20 percent of the body's glucose and oxygen, to support the energydependent synaptic activity of neurons. Brain energy metabolism decline is a hallmark event of cognitive decline, restoring energy metabolism as a novel therapeutic Neurodegeneration. 134 Blood glucose fluctuation, frequent hypoglycemia events, IR, and other metabolic disorders are all risk factors for regional energy metabolism decline in the brain. Diabetes has been found in existing studies to reduce cerebral glucose utilization and cause nerve damage, possibly by altering BBB glucose transport uptake, neurotransmitter metabolism, and the ability to regulate cerebral blood flow. 135,136 According to a study including 323 adults with prediabetes, hyperglycemia was negatively associated with 18F-FDG uptake in the prewedge lobe and occipital cortex. 104 The brain is inefficient at energy acquisition after glucose loading in obese men, which could be due to abnormalities in glucose transport across the BBB or downregulation of energy synthesis during mitochondrial oxidation. 137 The adaptive changes in brain energy metabolism were also observed in different animal models of diabetes. A recent multi-omics analysis in 4-month-old db/db mice of cognitive impairment has identified disturbances in cerebral and circulatory mitochondrial metabolism. 138 Huang et al. 139 found that 26-week-old db/db mice had significantly reduced mitochondrial function and ATP content in the hippocampus. Andersen et al. 140 found glucose hypometabolism in the cortex and hippocampal slices of db/db mice. The hippocampus showed enhanced ketone metabolism, and mitochondria in the cerebral cortex showed enhanced OXPHOS. These metabolic changes may be adaptive changes associated with low brain energy metabolism.
Astrocytes generate abundant mitochondrial reactive oxygen species, including lactic acid and serine, during glycolysis, which is coupled to neuronal OXPHOS to maintain brain energy requirements and relieve oxidative stress, and regulate the activity of neurotransmitter receptor. 39 Astrocytes' glucose uptake and glycolytic plasticity play an essential role in maintaining brain energy metabolic balance. Astrocyte metabolic disorders have been observed in various animal models of diabetes. Girault et al. 141 examined GK rats using 13 C magnetic resonance spectroscopy and found that T2D impairs glutamate-L-Glutamine circuits in the brain between neurons and astrocytes, increasing the rate of TCA astrocytes.
Biological communication between the gut and brain is mediated by the gut microbiome, regulating the system and cerebral energy balance. C57BL/6J mice treated with HFD antibiotics altered the gut microbiota and multiple metabolites and improved insulin signaling and energy metabolism in the brain. 142 Intermittent fasting (IF) can reconstitute the gut microbiota and metabolites of db/db mice, which in turn improves mitochondrial metabolism in the hippocampus and enhances genes associated with the OXPHOS pathway. 143 Akkermansia muciniphila CIP107961 and environmental enrichment has been shown to reverse the metabolic abnormalities in the brain induced by the high-fat, high-cholesterol diet. 144 Gut microbiota drives astrocyte activation along with metabolic switching, which in turn improves brain energy metabolism.
Gut microbiota promotes the expression of PFKFB3 and ATP1A2, key proteins of hippocampal ANLS. 145  Preclinical studies have observed that many anti-diabetic drugs drive astrocyte phenotypic transformation. IR deficiency in astrocytes leads to impaired glucose tolerance and increases anxiousdepressive behavior. Intranasal insulin administration improves cognitive function. 153 Astrocytes express IR and GLP-1R, which activation affects brain glucose uptake and neurocognitive function. As an intestinal hormone, GLP-1R agonists selectively block Aβ proteininduced microglia activation and inhibits astrocyte-responsive activation. 154 GLP-1R agonists also reduce astrocyte-derived activators to protect the BBB and inhibit neuroinflammation. 155 In addition, thiazolidinediones act as peroxisome proliferator-activated receptorγ (PPARγ) agonists and exert neuroprotective effects by inhibiting GFAP expression and morphological proliferation of astrocytes. 156,157 Currently, new drug developments such as the seaweed derivative sodium oligomannate (GV-971), have gone beyond neuronal centers and act by targeting the gut-brain axis. 158 Based on the broad utility of astrocytes and gut microbiota in neuroendocrinology, we take a step back and discuss those dietary interventions and natural compounds with considerable therapeutic potential.

| Dietary interventions and probiotics
Restructuring the dietary structure is a direct way to modulate the gut microbiota and explore its effects. Intensive lifestyle interventions have been recognized as an essential clinical approach to reversing the course of diabetes and delaying the development of complications. 159 Researchers' interest in nutritional psychiatry has driven many studies of specific dietary approaches such as the ketogenic diet, 160 the Mediterranean diet, 161 and Intermittent fasting 143 to improve neurocognitive function. Genomic and proteomic sequencing reveals extensive immune and metabolic shifts in arcuate nucleus astrocytes in response to a high-fat, high-sugar diet. 162 The ketogenic diet affects the metabolic plasticity of neurons and astrocytes, 163 and research has shown that gut microbiota is necessary and sufficient for the neuroprotective effects. 164 The calorie-restricted diet reduces astrocyte glycolysis thereby limiting neuroinflammation. 165 Astragalus polysaccharide (APP) possesses hypoglycemic and cognitive protective effects on both db/db mice 176 and STZ-induced diabetic models of rats. 177 APP increases the diversity of the gut microbiota, inhibits the potential intestinal pathogen Shigella, and enriches the beneficial bacteria Homococcus and Lactobacillus. 178 APP improves insulin resistance status in metabolically stressed mice and reduces astrocyte proliferation and activation around neuronal amyloid plaques. 179 Berberine (BBR) is characterized by low oral utilization and significant regulation in the intestinal microflora. It has been found in many plants, such as Coptis chinensis Franch and Phellodendron chinense Schneid. 180 BBR reduced hyperglycemia in diabetic rats while reducing oxidative stress in the hippocampus and preventing excessive activation of GFAP. 181,182 Curcumin and its analogs attenuate DCD by modulating inflammation and oxidative stress, and reduce aberrantly activated astrocytes in the hippocampus. 183,184 Curcumin reverses gut microbiota dysbiosis in diabetic rats, and increases Bacteroides and Bifidobacterium but inhibits Enterobacteriaceae and Thicketella phylum. 185 In vitro studies have shown that curcumin modulates the binding of endogenous ligands to AhR, promotes AhR activation, and decreases LPS-induced NF-κB activation, thereby regulating inflammatory astrocyte proliferation. 186 In addition, herbal active substances such as forsythoside B, rhubarb phenol, chrysin, resveratrol, and paeoniflorin have the effect of ameliorating DCD over gut microbiota and astrocytes, but direct and complete research evidence is still lacking.
Overall, the study of the gut-brain axis in traditional medicine still needs to shift from analyzing correlations to establishing causeeffect relationships. Observations on astrocytes have been mostly limited to neuroinflammation. Further enrichment of the modulatory effects of herbs on astrocyte phenotypes will help to uncover potential treatment of DCD and provide insight into the clinical efficacy of traditional herbals.

| CON CLUS ION
Though there is much evidence for cognitive impairment in patients with diabetes, the pathogenesis of DCD as a complication of diabetes is unclear and it is difficult to differentiate DCD from AD. Out of the multiple pathological factors, gut microbiota and its metabolites are important mediators to couple visceral and central environment, through the gut-brain axis neuroimmune pathway, the unique two-sided relationship between metabolic health and cognitive mind is highlighted. Unique anatomical and functional characteristics of astrocytes serve as intermediary glia in contact with circulating substances and brain microenvironment, maintaining immune and metabolic brain homeostasis and providing a continuous supply of energy-dependent neuronal activity. With the development of genomics and cell sequencing technology, "gut microbiotaastrocyte" axis research using the concept of system biology will help to deepen the understanding of the pathological mechanism of metabolic cognitive disorders, to explore an accurate and comprehensive treatment plan.

AUTH O R CO NTR I B UTI O N S
All authors read, revised, and approved the final manuscript.

ACK N OWLED G M ENTS
The authors' work in this area is supported by the Natural Science

Foundation of China (82274486); Science and Technology Research
Special project of Sichuan Provincial Department (2022YFS0382); Ren-song Yue's TCM studio. The schematic illustration was drawn by Figdraw.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.