2.1.1 Diet and Lifestyle

The initial colonization of gut microbiota in early life is determined by the mother, but subsequent changes are more influenced by environmental factors. Diet and lifestyle are recognized as critical determinants of gut microbiota composition [11, 12]. Changes in host nutrition induce temporary shifts in microbial composition, but major components such as meat, fish, and fiber can have a lasting effects, leaving characteristic specific bacterial patterns [13]. For example, a high-calorie, high-fat, low-fiber diet increases the abundance of Proteus species. Excessive intake of food additives can also impair blood glucose control and induce the proliferation of Proteus [14]. A long-term Mediterranean diet can partially mitigate age-related changes in gut microbiota composition and metabolic function, particularly unhealthy aging [15, 16]. Growing evidence shows that the composition and function of the gut microbiota are altered in obese individuals in both humans and rodents. FMT can shape host metabolism and impact obese phenotypes [17-19], demonstrating that diet-induced gut microbiota dysbiosis is a major cause of the disease rather than a consequence. In clinical trial cases, a low-fat and high-fiber diet strategy in ulcerative colitis (UC) patients can reduce inflammatory markers in the feces of patients and alleviate gut dysbiosis [20]. After a low-fat, high-fiber diet, the abundance of Bacteroides significantly increased, while Actinobacteria decreased in the feces of UC patients. The increase in Faecalibacterium prausnitzii and other microbes led to an anti-inflammatory shift in the microbiome. These findings support that long-term appropriate dietary interventions will be an effective approach to regulating gut microbiota dysbiosis.

2.1.2 Antibiotics and Other Medications

Antibiotic drugs have an inherent potential to promote dysbiosis through their antimicrobial activity. The most common effect of antibiotics on the gut microbiome are decreased phylogenetic diversity and richness. The increase abundance of Proteobacteria, including Enterobacteriaceae, leading to a proinflammatory state and enhanced bacteria expression of antibiotic resistance genes. Excessive antibiotic exposure in early life may have lasting negative effects on gut microbiota immunity, metabolism, and endocrinology. These effects could persist for years, potentially lasting into adulthood [21]. The use of macrolide antibiotics in children leads to a long-term reduction in Firmicutes and Actinobacteria, while increasing Bacteroidetes and Proteobacteria. Additionally, the recovery time of the microbiome's homeostasis is associated with the frequency of antibiotic use. Long time use may result in lasting alterations in the microbiota composition [22]. Antibiotic-induced dysbiosis can even alter the host transcriptome and m6A epitranscriptomic modifications through its metabolites [23]. Furthermore, exposure to other drugs or exogenous compounds can also cause gut microbiota dysbiosis [24]. In most cases, we only observe the correlation between exposure and disease outcomes, while the specific changes in the microbiota and their mechanisms of action still require further investigation. Although antibiotics are an important and essential medical tool, society must currently emphasize the long-term impacts of antibiotic overuse. Avoiding unnecessary antibiotic use is crucial for maintaining the ecological balance of the gut microbiota and preserving overall health.

2.1.3 Infections and Inflammation

Inflammation is the body's normal protective defense response to infection or injury. It is a driving factor for intestinal permeability and microbial dysbiosis. Pathogen infections, such as viruses and bacteria, can cause intestinal inflammation lead to dysbiosis. During the body's homeostasis, the gut microbiota maintains a diverse population of beneficial microorganisms (symbionts) to produce a balanced immune response. However, proinflammatory microbiota (pathogenic bacteria) may decrease or increase during dysbiosis. This changes shifting the balance between proinflammatory and anti-inflammatory responses toward an inflammatory phenotype associated with various diseases, such as multiple sclerosis (MS) and inflammatory bowel disease (IBD) [25]. Generally, Intestinal immunity stimulates the occurrence of intestinal inflammation and protects the body from harmful pathogens. But excessive activation of Th cells promotes the progression of intestinal inflammation [26]. Infection by foreign microorganisms trigger changes in the composition of the microbiota may cause a series of events. The enrichment of pathogenic bacteria and the release of harmful toxins lead to proinflammatory environment and impaired intestinal barrier function [27]. For example, Klebsiella pneumoniae crosses the mucosal layer to invade intestinal epithelial cells. And then activate host macrophages to release inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). This heightened proinflammatory state disrupts intestinal homeostasis, leading to an imbalance in the microbial environment [28].

2.1.4 Host Genetic Predisposition

In addition to environmental factors, host-specific factors (such as host genetics) can influence the composition of the gut microbiota. Some genetic variations in the host may make individuals more susceptible to dysbiosis, which is an important factor in the development of metabolic and immune-related diseases. A study analyzing the gut microbiome and human variation in the TwinsUK cohort, which included 250 individuals, identified microbiome-related metabolic traits (e.g., body mass index and blood pressure) as well as common microbial functions (such as secretion system proteins and antibiotic resistance) associated microbiome-related diseases. For example type 2 diabetes mellitus (T2DM) and some neurological disorders were associated with host genetics. The genetic loci of solute carrier family 22 member 5 (SLC22A5), G protein-coupled receptor 35 (GPR35), and GPR65 are associated with the risk of IBD onset and host–microbe interactions [29]. Genetic similarities in the microbiome have been identified in twin and familial population genetic studies, particularly in the phyla Firmicutes and Verrucomicrobia [30]. Besides, variants in certain individual genes can directly affect the composition of the gut microbiota. For example, the lactase (LCT)locus is associated with Actinobacteria and Bifidobacterium, while interactions exist between ABO and fucosyltransferase 2 (FUT2) variants and bacterial abundance [31]. Establishing the relationship between host genetic susceptibility and gut microbiota dysbiosis is instrumental in understanding the relationship between gut microbiota imbalance and the development of diseases. On the one hand, genetic variations may directly lead to disease phenotypes, which in turn can trigger changes in the microbiome. On the other hand, they may directly alter the microbiome lead to disease phenotypes. Microbiome-wide association genetic studies are expected to identify additional host genetic variations that influence disease progression by disrupting the microbiome composition. It will provide a clearer explanation of the interplay between genetic susceptibility and gut microbiota dysbiosis.

2.1.5 Differences in Intestinal Flora Among Different Populations

An early study based on metagenomic sequencing analysis compared the gut microbiome composition of populations from different geographical regions (such as the United States, Europe, Africa, and Asia) [32]. Although all populations share a common microbiome, there are significant differences in the gut microbiome details across different regions. These differences may be closely related to factors such as dietary habits, environmental factors, and genetic background. In addition, differences in gut microbiome composition are also observed across different age groups, with gut microbiome diversity significantly decreasing as age increases [33]. Infants have a characteristic microbiome before weaning, which then transforms into a more diverse microbiome with the introduction of solid foods. As individuals age, the microbiome becomes relatively stable until late adulthood (around 65 years), after which diversity peaks and begins to decline, becoming more pronounced in individuals over 80 years old [34]. In the elderly population, changes in a diverse microbiome (including organisms suspected of producing anti-inflammatory metabolites such as SCFAs) are closely associated with enhanced inflammatory responses and the occurrence of chronic diseases. Others, the composition of the gut microbiome also shows significant differences in populations with unhealthy conditions. For example, obese patients have lower gut microbiome diversity and a specific microbial composition, such as an imbalance in the ratio of Firmicutes to Bacteroidetes [35], which also highlights the potential link between gut microbiome dysbiosis and obesity. Besides, compared with healthy controls, specific types of bacteria (such as certain anaerobes) are more abundant in diabetic patients [36], and the dysbiosis of these microbial populations is closely associated with insulin resistance and metabolic abnormalities.

Existing research on gut microbiome dysbiosis mostly focuses on specific populations or single disease models, lacking cross-sectional comparative studies on dysbiosis across different populations or conditions. Incorporating cross-population studies can significantly enhance the understanding of how gut microbiome dysbiosis varies across different genetic backgrounds, lifestyles, dietary habits, and environmental conditions. This will help reveal the general patterns of gut microbiome dysbiosis and its impact on the health of different populations.

2.2.1 Microbial Metabolite Imbalance

Dysbiosis of the gut microbiota not only leads to changes in the composition of the microbial community but also results in alterations of metabolites. The gut microbiota can regulate the body's nervous system by influencing the gut–brain axis. The study found that a humid and hot environment induces gut microbiota dysbiosis, such as a decrease in the abundance of Lactobacillus murinus, which causes an increase in the levels of secondary bile acids (BAs). This in turn triggers the elevated expression of proinflammatory cytokines and increased neuroinflammation, ultimately promoting the progression of anxiety disorders [38]. The genus Akkermansia is a key factor in the production of SCFAs. Gut microbiota dysbiosis causing a reduction in Akkermansia, resulting in decreased SCFA synthesis. The reduced abundance of Akkermansia and SCFAs increases the likelihood of adults developing hypertension and cardiovascular diseases [39]. Besides, the dysregulation of the gut microbiota and the subsequent reduction in SCFA synthesis promote the onset of neurological diseases. The decrease in butyrate among the SCFAs increases inflammation in the brain and inhibits microglial maturation. Those guide the oligomerization of amyloid-beta (Aβ) 1–40, which contributes to the development of Alzheimer's disease (AD) [40]. The deficiency of propionate inhibits the survival of dopaminergic cells and the growth of neurites. Furthermore, increasing neuroinflammation promote the onset and progression of Parkinson's disease (PD) [41]. Tryptophan is an important metabolite derived from gut microbiota, aberrantly activates the AHR signaling pathway as a ligand. It will influence the progression of cardiovascular diseases and chronic kidney disease [42]. Indolepropionic acid (IPA) is a tryptophan metabolite involved in renal immunoregulation in hypertensive patients. When IPA is reduced in the dysbiosis, it leads to an increase in Th17 cells and decrease in T-regulatory (Treg) cells, ultimately leading to elevated blood pressure [43]. In addition, dysbiosis of the gut microbiota inhibits the production of vitamin D3, thereby leading to hypertension [44].

2.2.2 Impaired Intestinal Barrier Function

A healthy human gut has a certain degree of permeability. This property allow nutrients to pass through while maintaining its barrier function to prevent potentially harmful substances from leaving the gut and spreading throughout the body. When the gut microbiota is dysregulated, it can lead to increased intestinal permeability, triggering the development of GI diseases. Intestinal barrier dysfunction is referred to as “leaky gut” or intestinal permeability syndrome. Commonly, disruption of intestinal barrier integrity is one of the characteristics of IBD. The study found that a decrease in SCFAs caused by gut microbiota dysbiosis leads to increased intestinal permeability. This change increases the likelihood of developing IBD [45]. Moreover, the increased intestinal permeability is closely associated with the later stages of Crohn's disease (CD) progression [46].The impairment of gut barrier function not only affects GI disorders but also impacts CNS diseases [47]. Increased intestinal immune/inflammatory responses caused by intestinal flora imbalance can damage the integrity and permeability of the intestinal barrier function. Next, it triggers CNS inflammation and neurodegenerative processes contribute to the occurrence of PD [48]. A high-fat diet can impair intestinal barrier integrity in mice, leading to changes in glial cells, a reduction in dendritic spines of neurons, and behavioral changes consistent with depression and anxiety phenotypes [49]. Intestinal barrier disruption can affect the function of microglial cells in the CNS through the gut–brain axis, leading to the onset of MS [50]. In addition, due to the disruption of the intestinal barrier, inflammatory responses occur in the mesenteric lymph nodes, which cause the liver inflammation. Persistent hepatic inflammation can trigger excessive activation and proliferation of hepatic stellate cells to form liver fibrosis [51]. Clinical studies have shown that the loss of barrier integrity is closely associated with metabolic disorders, including obesity and T2DM [52]. At the same time, it will lead to metabolic endotoxemia, which is considered a major factor in insulin resistance and obesity [53].

2.2.3 Immune System Dysregulation

The disruption of the intestinal barrier caused by gut microbiota dysbiosis further triggers an imbalance in the intestinal microenvironment's immune response. This change contributes to the development of various diseases with the uncontrolled growth of harmful microorganisms. Changes in the gut microbiota are associated with various systemic autoimmune diseases. Dysbiosis of the gut microbiota causes an increase in parasitic bacteria (segmented filamentous bacteria), which trigger arthritis by promoting the elevation of Th17 cells and the production of autoantibodies [54]. Additionally, Cellulomonas flava (CFB) affects the Th17/Treg balance to influence immune homeostasis and contributes to autoimmune diseases [55]. Type 1 diabetes (T1DM) is a systemic autoimmune disease associated with microbial dysbiosis. It is characterized by an abundance of bacteria that produce acetate and propionate in the gut microbiota, which in turn impairs neutrophil function in patients with T1DM [56]. Besides, gut microbiota dysbiosis plays a potential role in the development of MS. The increase of proinflammatory bacteria induces Th1/Th17 differentiation, which can systematically spread to the brain and lead to an increase in inflammatory factors [57]. The symptoms of autoimmune diseases can be partially improved by giving probiotics and prebiotics to mice. Therefore, understanding the impact of gut microbiota on immune system dysregulation plays an important role in the treatment of diseases (Table 1).

3.1.1 Irritable Bowel Syndrome

IBS is a condition that affects intestinal motility, intestinal nerve sensitivity, or the brain–gut interaction in controlling these functions [94]. Although it does not increase mortality, but it significantly reduces the quality of life. Moreover, no clear and effective treatment is available. The study found that IBS patients exhibit lower bacterial diversity, indicating dysbiosis of the gut microbiota. A randomized double-blind clinical trial evaluated the efficacy of FMT in treating IBS patients. The report indicated that improve gut dysbiosis could alleviate IBS symptoms and improve patients’ quality of life [95]. There is also growing evidence suggesting a causal relationship between the gut microbiome and human metabolic health. Studies on human subjects and preclinical monkey models of metabolic syndrome have indicated that gut bacteria Ruminococcus gnavus-derived tryptamine and phenylethylamine play a pathogenic role in insulin resistance induced by gut microbiota dysbiosis in T2DM and IBS. Tryptamine and phenylethylamine produced by Ruminococcus gnavus-mediated dietary amino acid catabolism impair insulin sensitivity by activating the TAAR1–MAPK/ERK signaling axis. It leads to insulin resistance in gut dysbiosis-related IBS and T2DM [59]. More and more precise research on different subtypes of IBS has increasingly revealed distinct gut microbiome characteristics. Different subtypes have distinct bacterial characteristics, and the associated functional changes are related to the pathogenesis of IBS. For example, the production pathway of hydrogen sulfide is upregulated in IBS with diarrhea, whereas the biosynthesis pathway of palmitic acid is enhanced in IBS with constipation [96]. These results further support the regulatory role of the gut microbiota in IBS.

3.1.2 Inflammatory Bowel Disease

IBD is a group of heterogeneous chronic inflammatory diseases caused by the interaction of genetic factors, environmental factors, and the gut microbiota. IBD typically including UC and CD [97, 98]. Under healthy physiological conditions, symbiotic microorganisms produce beneficial metabolic products that help maintain an impermeable barrier composed of intact mucosa and epithelium. When genetic/immune driving factors, environmental triggers, and lifestyle/dietary changes lead to the onset of a predisease stage, some symbiotic microorganisms transform into pathogenic bacteria that are better adapted to the ecological niche of the ecosystem. As the disease progresses, IBD patients exhibit active inflammatory mucosal damage. The massive emergence and proliferate of pathogenic bacteria leads to the quantity of symbiotic bacteria significantly decrease and a sharp reduction in beneficial metabolites with persistent inflammatory infiltration. Persistent inflammation and long-term dysbiosis cause immune imbalance and impaired mucosal healing, thereby sustaining inflammation and dysbiosis in a chronic cycle [99]. The intestinal barrier is mainly composed of digestive fluids, symbiotic bacteria, antimicrobial peptides, epithelial cells, and local immune cells. In the case of IBD, bacteria such as R. gnavus will degrade mucins in large amounts and disrupt the integrity of the epithelium. The amplification of Enterococcus faecalis promotes the production of matrix metalloproteinases (e.g., gelatinase), which degrade E-cadherin and impair mucosal integrity. At this point, harmful GI bacteria or related toxins, antigens, and so on break through the barrier and translocate. After being phagocytosed by immune cells, a large amount of lipopolysaccharides (LPS) has being released to guide chronic inflammation [100]. At the same time, gut microbiota dysbiosis leads to an imbalance in microbial metabolites, such as BA, SCFAs, tryptophan, medium-chain fatty acids, and trimethylamine N-oxide (TMAO). These metabolites regulate the activation of the NLRP3 inflammasome, the secretion of inflammation-related cytokines, the differentiation of naïve T cells into Treg or Th17 cells, and the trafficking of lymphocytes to extraluminal sites, thus further mediating the composition of the gut microbiome [101].

3.1.3 Colorectal Cancer

Among GI diseases, CRC as the third most common malignancy globally is closely associated with the gut microbiota. Dysbiosis, specific pathogenic microorganisms, metabolites, virulence factors, and microbial carcinogenic mechanisms all contribute to the occurrence and development of CRC [102, 103]. For example, the pathogenic bacterium Alistipes increases, while the probiotic Parabacteroides distasonis decreases under a high-fat diet, leading to impaired gut barrier function. Those changes promote colorectal tumorigenesis in germ-free mice, indicating that the gut microbiota plays a crucial role in high-fat diet-associated CRC development [104]. Besides, gut microbiota metabolites such as taurodeoxycholic acid can activate the carcinogenic MAPK/ERK pathway in colonic epithelial cells to promote colon cell proliferation [61]. SCFAs can antagonize CRC cell proliferation, accelerate its apoptosis, and inhibit inflammation-related CRC carcinogenic pathways [104]. At the same time, they activate drug-metabolizing enzymes and inhibit the degradation of primary BAs into secondary BAs, what reduce the burden of carcinogens such as BAs [105]. The functions of SCFAs are various, they can act as tumor suppressors by regulating the expression of oncogenes through epigenetic effects during the progression of CRC [106]. Multiomics studies have also revealed the potential application of gut microbiota metabolites in early CRC screening and diagnosis, including various metabolite combinations such as l-valine, myristic acid, and others [107-109]. In recent years, several studies have focused on gut microbiota-related biomarkers for noninvasive diagnosis of CRC and its precancerous lesions. For example, the abundance of Fusobacterium nucleatum is significantly increased in patients with CRC and precursor lesions [110, 111]. Additionally, the DNA of Fusobacterium nucleatum in oral saliva is an independent factor for predicting the prognosis of CRC [112]. Gut microbiome biomarkers have potential translational application value in the screening and early diagnosis of CRC.

3.2.1 Obesity and Type 2 Diabetes Mellitus

Rapidly changing lifestyles in recent years have exacerbated obesity and the occurrence of obesity-related diseases. The changes in the gut microbiome caused by obesity have become a potential driving factor for related comorbidities [113]. Diabetes mellitus (DM) is a group of diseases that affect blood glucose regulation. T1DM is caused by an autoimmune response targeting pancreatic β cells, whereas T2DM is characterized by the body's inability to properly produce or use insulin. In T2DM, the gut microbiota is closely associated with the development of the disease. The study confirmed that the gut microbiota composition of T2DM patients has changed [114], and the use of hypoglycemic medications improved the diversity and richness of the gut microbiota. It played a positive role in the treatment of T2DM patients by enriching the intestinal ecosystem with beneficial bacteria. Therefore, the development of T2DM has a subtle interplay with gut microbiota homeostasis. Compared with healthy person, the abundance of Firmicutes and Clostridium butyricum was significantly lower in T2DM patients. Additionally, the ratio of Bacteroidetes to Firmicutes and Bacteroides-Prevotella to Clostridium coccoides-Eubacterium was positively correlated with blood glucose levels [115]. The occurrence and development of T2DM is associated with elevated levels of inflammatory factors, including increased LPS in peripheral blood [116]. LPS can bind to the Toll-like receptor 4 (TLR4) receptor to trigger macrophage aggregation and activate the NF-κB signaling pathway. This interaction leads to the release of inflammatory factors and inhibit insulin secretion. In addition, the metabolites SCFAs participate in glucose metabolism pathways through various signals. SCFAs can bind to the free fatty acid receptors FFAR2 or FFAR3 on intestinal L cells, stimulating the release of glucagon-like peptide 1 (GLP-1) and peptide YY. It can promote insulin secretion and reduces glucagon levels [117]. When T2DM occurs, low-grade inflammatory infiltration leads to impaired intestinal barrier function. Butyrate produced by gut microbiota plays a crucial role in maintaining the integrity of the intestinal barrier. SCFAs are also important anti-inflammatory mediators that can limit autoimmune responses by promoting the generation of regulatory T cells [118]. Therefore, the balance of its metabolic products is easily altered when the dynamic balance of gut microbiota is skewed. This unbalanced state can easily promote the occurrence and progression of T2DM.

3.2.2 NAFLD and Gut–liver Axis

Dysbiosis of the gut microbiota repeatedly occurs in obesity and T2DM, both of which are closely associated with NAFLD. The global burden of NAFLD is primarily caused by the dual epidemics of obesity and T2DM [119]. The comorbidity rate of obesity/T2DM and NAFLD is as high as 70–80%, and the incidence of NAFLD is 100% in obese patients with T2DM [120]. The metabolites of the gut microbiota promote the development of NAFLD through multiple pathways. BAs are involved in NAFLD by regulating hepatic and extrahepatic lipid, carbohydrate, and inflammatory pathways by targeting BA receptors [121]. Evidence suggests that inhibiting the production of ceramide in the intestine can reduce lipid accumulation in the liver, thereby preventing high-fat diet-induced NAFLD [122]. Specific bacterial traits directly indicate the persistent enrichment of Proteobacteria in steatosis and nonalcoholic steatohepatitis, directly affecting histidine and its metabolite levels [123]. Clostridia and Lactobacillus genera also exhibit overlap in NAFLD and T2DM [124]. Overall, dysbiosis directly leads to increased intestinal permeability to bacterial products in metabolic diseases, resulting in higher levels of these products in the systemic circulation. Dysbiosis combined with poor diet can also alter the intraluminal metabolism of substrates such as food. This will increase production of certain SCFAs and consumption of choline to exacerbate the disease progression. Currently, an increasing number of studies focus on the relationship between gut microbiota or its specific metabolites and diseases. For example, histidine is negatively correlated with the level of fatty degeneration, and it is a metabolite with high disease predictive capability [123]. Predicting the relationship between differential microbiota, metabolites, and diseases will contribute to the development of prevention and treatment strategies for such diseases.

The establishment of the gut–liver axis facilitates bidirectional crosstalk between the GI tract and liver metabolism in health and disease. The hepatic portal vein collects blood from the small intestine, large intestine, spleen, and pancreas. It is a hallmark anatomical structure for digestive tract–liver communication. In turn, the liver secretes BAs into the intestine via the biliary system, which are reabsorbed in the intestine. This enable bidirectional communication along the liver–gut axis [125]. For example, the metabolism of BAs by gut microbiota enables their involvement in diverse host regulatory processes and activates innate immune genes in the small intestine, resulting in direct or indirect modulation of the gut microbiota [126]. Gut microbiota dysbiosis and intestinal barrier dysfunction may lead to systemic microbial translocation and entry into the hepatic portal circulation [127] to promote the liver diseases. BAs metabolism in the gut–liver axis is mainly regulated by Farnesoid X receptor (FXR) and G protein-coupled BA receptor. These receptors have been clinically applied in the treatment of liver-related diseases. For example, the most widely used FXR agonists primarily include BAs derivatives, steroidal compounds, and nonsteroidal compounds. It activates FXR to inhibit the production and influx of BAs and promotes the outflow, thereby alleviating the excessive accumulation of BAs in the liver [128]. A comprehensive understanding of the interactions within the gut–liver axis plays a positive role in disease treatment to help establish a multidimensional approach to therapy. Scientists no longer limit their focus to a single organ or component but instead adopt a holistic perspective to construct an entire biological network, including the establishment of the gut–liver–brain axis. In the future, under the framework of the macro-network, more detailed exploration and mechanistic explanations will be needed, supported by high-quality preclinical studies and clinical randomized controlled trials to further develop targeted therapeutic drugs.

3.3.1 Alzheimer's Disease

Currently, changes in the composition of gut microbiota have been linked to various neurological disorders, although the causal relationship between gut dysbiosis and neurological dysfunction remains elusive. For example, gut microbiota dysbiosis may promote Aβ aggregation, neuroinflammation, oxidative stress, and insulin resistance. All of those promote the onset of AD [137]. AD is a progressive neurodegenerative disorder of the CNS, characterized by a gradual decline in cognitive abilities. The deposition of extracellular Aβ forms amyloid plaques, and the accumulation of intracellular hyperphosphorylated tau forms neurofibrillary tangles remain the primary neuropathological criteria for AD diagnosis. Since Hardy and Higgins first proposed the amyloid cascade hypothesis in 1992, which suggests that the accumulation of Aβ peptides derived from the amyloid precursor protein is the initial event in the pathogenesis of AD [138]. This hypothesis has remained the dominant theory of AD pathogenesis. In the subsequent long-term development, an increasing amount of evidence suggests that neuroinflammation is not just a result of AD, but also an important factor in its onset and progression. This has driven research into the role of the microbiome–brain–gut axis in AD. The imbalance of gut microbiota indirectly promotes the development of AD.

The gut microbiota is an important environmental factor for microglia to function in immune and neurological responses throughout the host's life cycle. Evidence suggests that the gut microbiota is essential for the AD pathology and cognitive deficits in AD mouse models [139]. Studies in model animals report that gut dysbiosis may contribute to neuronal damage in AD through Aβ-dependent mechanisms. For example, in AD mouse models, abnormal accumulation of Aβ in myenteric neurons and activation of innate immunity in the gut precede the onset of CNS neuroinflammation [140]. Similarly, in Tg2576 mice (a transgenic mouse model of AD), gut microbiota dysbiosis, intestinal epithelial barrier dysfunction, and intestinal vascular Aβ deposition occur precede the onset of brain Aβ deposition [141]. Aβ deposits have also been found in the intestinal autopsies of AD patients [141]. All of those suggest that the onset and progression of AD are closely linked to the gut microbiota. SCFAs effectively interfering with Aβ assembly [142], but the derivative metabolite TMAO increases β-secretase activity, thereby exacerbating the accumulation of Aβ [142]. In addition, the increase in BAs can disrupt tight junctions and increase the permeability of the BBB [143]. It allows more peripheral blood products to enter the CNS. In sum, the imbalance of gut microbiota indirectly promotes the development of AD.

3.3.2 Parkinson's Disease

PD is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the brain. A prominent pathological feature is the abnormal aggregation of α-synuclein (α-syn) in CNS. And the death of dopaminergic neurons impairs dopamine production to limit the capacity for neural innervation in PD. The primary dopamine synthesis pathway in the human body involves the phenylalanine–tyrosine–l-dopa–dopamine pathway, which supplies dopamine to the brain. In this process, tyrosine hydroxylase (TH) acts as a rate-limiting enzyme, hydroxylating tyrosine to produce l-dopa in the presence of the cofactor tetrahydrobiopterin (BH4) [144]. And then it converted to dopamine in the brain. Dopamine is a catecholamine neurotransmitter that plays a critical role in motor coordination, as well as in motivation, reward, addiction, learning, and memory. Studies have found that Enterococcus species possess abundant TH activity, and improving the gut microbiota can increase dopamine levels in the brain to alleviate PD's symptoms. This is closely associated with l-dopa produced by gut bacteria entering the brain through circulation and being converted into dopamine [145]. This directly links the gut microbiota to brain function.

Population studies have shown that gut microbiota undergoes continuous changes with the progression of PD [146]. A study involving 490 PD patients revealed the relationship between PD and the gut microbiome through metagenomic analysis. In PD patients, the composition of the gut microbiota is predominantly pathogenic. It is characterized by an increase in pathogens and immunogenic components, dysregulation of neuroactive signals, induction of α-syn pathological aggregation, and a reduction in anti-inflammatory and neuroprotective factors [147]. Inflammation is considered a driving factor in the pathogenesis of PD. Modulating the gut microbiota can reduce systemic inflammation by improving intestinal inflammation and gut barrier function. Evidence suggests that FMT can protect against brain local neuroinflammation mediated by the LPS–TLR4 signaling pathway in an MPTP-induced PD mouse model through the gut–brain axis [148]. In clinical randomized controlled trials, FMT treatment not only improved GI symptoms in PD patients but also effectively alleviated motor dysfunction [149]. Gut microbiota metabolites are also involved in the progression of PD. For example, SCFAs are associated with α-syn aggregation specific to Thy1–αSyn genotype mice. It pathologically activates microglia, exacerbates neuroinflammation, and promotes motor dysfunction in PD [73]. Studies on PD patients have also demonstrated that low levels of SCFAs are associated with the progression of PD. It is linked to inflammation development supported by SCFAs and disruption of the gut barrier [150-152]. In addition, free fatty acid receptor 3 (FFAR3)in the ENS also mediates the neuroprotective effects of propionate in PD [153].

As the role of the microbiome–gut–brain axis in PD receives increasing attention, more clinical studies are needed to explore the relationship between gut microbiota changes and the clinical subtypes of PD. Currently, Only little studies have explored differences in gut microbiota among different motor subtypes of PD by performing metagenomic sequencing on fresh stool samples from PD patients [154]. With the development of big data, more technological approaches will available for detecting gut microbiota and their metabolites. Establishing a gut microbiome profile network for PD populations will better contribute to the prevention and treatment of PD.

3.3.3 Autism Spectrum Disorder

With the development of gut microbiota and the gut–brain axis, more interrelations between diseases have come into focus. The prevalence of GI disorders in patients with autism spectrum disorder (ASD) is as high as 70% [155]. These data prompted many studies to link the frequently observed gut microbiota dysbiosis in ASD patients to the regulation of brain function and social behavior. ASD is a group of complex neurodevelopmental disorders characterized by reduced speech, social interaction, and repetitive behaviors with restricted activities. Interestingly, approximately 43–76% patients with ASD have abnormal intestinal permeability [156]. But the incidence of GI symptoms, including abdominal pain, bloating, constipation, and gastroesophageal reflux, is as high as 84% in pediatric patients [157]. It suggest that the microbiome–gut–brain axis may play an important role in the pathology of ASD. The researchers found that when germ-free mice were colonized with the fecal microbiota from children with ASD, the mice exhibited significant ASD-like behaviors, demonstrating that the microbiota plays a pathogenic role in ASD [158]. About 20 years ago, the potential link between the microbiota and ASD was proposed. There have been reports that oral vancomycin treatment provided short-term benefits to a small number of children with ASD [159].

The gut microbiota can influence gene expression and host behavior through various pathways, including the production of neuroactive molecules. For example, the gut microbiota specifically regulates the concentrations of several metabolites in the colon and circulatory system, such as taurine (a metabolite of cysteine or taurocholic acid) and 5AV (a fermentation product of proline) [160]. Taurine is crucial for brain development and can be produced by neurons and astrocytes. 5AV acts as an anticonvulsant in mice and these metabolites mediate communication between the gut and the brain [158]. GABA is an amino acid and the main inhibitory neurotransmitter in the brain. The altered GABA pattern has been identified as a key feature of the neurophysiology in ASD patients [161], while Bifidobacterium and Lactobacillus are producers of GABA [162]. This prove homeostasis of the gut microbiota plays an important role in the production and maintenance of GABA homeostasis. In addition to changes in intestinal permeability and gut microbiota metabolite-mediated neuronal activity, immune system defects in ASD patients are associated with alterations in the composition of the gut microbiota. The composition of gut microbiota changes to increase proinflammatory factors such as interferon (INF), IL-6, IL-8, and IL-1b in the brains of ASD patients [163], thereby activating microglia and initiating an immune response. These highlight the important role of the gut microbiome in brain communication, and it may serve as a potential therapeutic target in ASD.

3.5.1 Cardiovascular Diseases

It is generally believed that the risk factors for cardiovascular diseases include hypertension, atherosclerosis, obesity, diabetes, and so on. However, with the establishment of the network of diseases, it has been discovered that the microbiome plays a role in cardiovascular health [179, 180]. The gut microbiome is involved in the metabolism of choline, phosphatidylcholine, carnitine, and produce TMAO at last. TMAO not only regulates cholesterol balance and BAs levels [181] but also activates the MAPK and NF-κB signaling pathways [182]. In addition, the common metabolite LPS can induce vascular oxidative stress by activating the TLR4 pathway. This phenomenon induce endothelial dysfunction and vascular inflammation. Apart from this, the gut microbiota can metabolize polysaccharides and proteins into SCFAs, which are closely related to cardiovascular diseases. Specifically, propionate and butyrate have been shown to protect the host from hypertension-related cardiovascular damage [183, 184]. Additionally, the action of SCFAs on G protein-coupled receptors [185] further strengthens the role of gut microbiota in blood pressure regulation and cardiovascular diseases progression.

3.5.2 Skin Disorders

Based on the establishment of the gut–skin axis, the important role of microbiota in maintaining skin homeostasis has become clear. When the harmonious relationship between the gut microbiota and the immune system is disrupted, it subsequently affects the skin and promotes the development of skin diseases. For example, the occurrence of atopic dermatitis in infancy is related to the content of arachidonic acid in breast milk. High concentrations of arachidonic acid induce dysbiosis in the infant, significantly increasing the area of skin lesions [89]. Besides, Faecalibacterium prausnitzii, Akkermansia muciniphila, and Ruminoccocus prevent the colonization of pathogenic bacteria on the skin to prevent psoriasis by competitive inhibition and enhancing the production of SCFAs [186-188]. Generally, the communication between the gut and skin is established through immune crosstalk, through the immune system cooperating to manage systemic or local inflammatory responses [189]. A good example is that the reduction in the number of potentially beneficial microorganisms in psoriasis disrupt the balance of the immune system. The decrease of Bacteroides and Proteobacteria exacerbating the occurrence of proinflammatory responses [190]. In sum, a deeper understanding of the potential mechanisms of the gut–skin axis and the connection between the gut and skin diseases can provide guidance for healthy skin management and the establishment of a healthy gut microbiota. It also will to assist in the search for drugs related to the treatment of skin diseases.

3.5.3 Respiratory Diseases

The gut–lung axis is a complex system that connects, modifies, and influences the microbiota from the GI tract to the lungs. Bacterial products of the gut microbiota may cross the epithelial barrier into the blood and regulate the gut–lung axis [191]. The lung and intestine demonstrate a bidirectional relationship, with a hallmark characteristic of interconnected immune and inflammatory regulatory networks. On the one hand, soluble components or metabolites of gut microbiota influence lung diseases through immune regulation. As a key component of SCFAs produced by gut microbiota, butyrate has been shown to exert significant effects on a range of pulmonary diseases, such as allergic asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis [192, 193]. These metabolites are capable of activating GPCRs (HCAR2/GPR109a, FFAR2/GPR43, and FFAR3/GPR41) located on the intestinal epithelial cell surface or undergoing internalization via cellular transporters. SCFAs can be utilized for ATP generation in the mitochondria, act as HDAC inhibitors in the nucleus, or be transported out of the cell and into the lamina propria, subsequently entering the bloodstream. Therefore, SCFAs can regulate the functions of various target tissues, including the lungs, kidneys, and brain. At the same time, it can regulate immune cells, inducing lymphocyte tolerance and participating in inflammatory regulatory networks [194].

On the other hand, lung and gut microbes interact by altering the immune system. Both intestinal and airway mucosa express common homing chemokine receptors, such as chemokine ligand 28 (CCL28), which mediate lymphocyte migration [195]. Gut-associated lymphoid tissue is an important link between the lungs and intestines, playing a key role in inducing immunity and controlling communication between the intestinal mucosa and systemic immunity [196]. The mucosal surfaces of the lungs and intestines are rich in group 2 innate lymphoid cells (ILC2s). ILC2s mature through the lung-gut axis to acquire normal functions. Developmental defects of ILC2s in the lungs significantly affect the number and function of ILC2s in the intestine [197]. Allergens that promote asthma increase the number of ILC2s in the lungs and intestines, indirectly proving the correlation between the lungs and the intestines. Clinical studies also indicate that asthma and UC are associated with IL-33 signaling-mediated intestinal inflammation, particularly in individuals under the age of 16 years [198]. NF-κB inflammatory signaling disrupts lung fibrosis caused by gut–lung microbiota dysbiosis in the context of diabetes by supporting mucosal immune crosstalk [199]. The interactions between the gut microbiota and its metabolites with the immune system promote the development of pulmonary diseases. The establishment of bidirectional communication between the gut–microbiota–lung axis has enhanced the understanding of treatments for pulmonary diseases. For example, targeting the gut microbiome can significantly improve acute lung injury caused by LPS [200]. Probiotic supplementation can improve lung function and has a beneficial effect on COPD [201]. Additionally, specific microbiomes have been found to effectively predict the responsiveness of patients to immunotherapy in lung cancer patients [202]. And the survival of non-small cell lung cancer patients is associated with gut bacterial diversity [191]. The development of the gut–lung axis has deepened our understanding of respiratory diseases. Apart from this, the interaction between the microbiome and cancer treatment has opened new avenues for improving efficacy and reducing side effects.

3.5.4 Placental-Origin Diseases

The maternal microbiome is a critical regulator of health during pregnancy and has a significant impact on offspring development [203, 204]. Microbiota or microbial metabolites are emerging as potential modulators of placenta-related prenatal diseases, such as fetal growth restriction, preeclampsia, and preterm birth. The mother and fetus establish extensive connections through the highly vascularized placenta. The placental labyrinth consists of maternal and fetal blood spaces, separated by trophoblast cells, the basement membrane and fetal endothelial cells. Together, these structures mediate gas and nutrient exchange to sustain fetal growth and development [205]. Therefore, the maternal gut microbiota regulates not only the metabolites within the mother but also those of the fetus itself. Studies have found that the functional metabolites produced by the maternal gut microbiota during pregnancy are critical for supporting placental growth and angiogenesis in mice [206]. Moreover, supplementation with SCFAs during pregnancy can prevent placental growth restriction and vascular dysfunction in maternal malnutrition model [206]. In an obese pig model, a reduction in maternal gut microbiota diversity was also shown to lead to decreased SCFAs, inducing placental oxidative damage and mitochondrial dysfunction [207]. At the same time, the placenta mediates the SCFAs transfer from maternal circulation to fetal circulation to promote fetal neurodevelopment [208]. In a sheep model, gut microbiota dysbiosis caused by maternal environmental pollutants promotes placental cell apoptosis in pregnant ewes through the gut–placenta axis. It leads to fetal growth restriction [209]. The impact of environmental pollutants on pregnants and fetuses is often closely related to the gut–placenta axis. Population studies show that microplastics cause maternal gut microbiota dysbiosis and enter the placenta to disrupt offspring development [210]. Reduced gut microbiota diversity in children aged 4–6 years is often associated with prenatal exposure to environmental pollutants and their accumulation in the placenta [211]. Tracing back to early life, intrauterine fetal growth and development heavily depend on adequate placental function. Poor maternal gut microbiota is associated with impaired placental homeostasis and fetal development. The most direct evidence is that maternal Bifidobacterium promotes placental morphogenesis and regulates fetal growth through the gut–placenta axis [212]. Moreover, maternal gal-3 deficiency-induced gut microbiota dysbiosis leads to fetal growth restriction too [213]. It is clear that changes in the maternal gut microbiota and metabolites may lead to impaired placental adaptation. And changes in the gut–placenta axis can cause developmental alterations in the offspring [214].

With the development of genomic technologies such as metagenomics, metatranscriptomics, and metaproteomics, it may be possible to predict the characteristics of the placenta-associated microbiome [215, 216]. It could serve as therapeutic targets for placenta-related diseases. With the rapid development of big data, it may be possible to construct gut–placenta data networks across different ethnic backgrounds. This work will contribute to fully understand the importance of host–microbiome symbiosis during pregnancy. Combine AI to predict microbiome-related target changes, the drugs and probiotics that regulate the balance of the gut microbiota to modulate the gut–placenta axis may become new candidate approaches for alleviating gut-derived placental damage or fetal growth restriction (Figure 3).