In the intestine, intestinal microbiota digest oligosaccharides, polysaccharides, peptides, proteins, and glycoproteins to create SCFAs, primarily butyric acid, propionic acid, and acetic acid. SCFAs have been proven in studies to regulate blood glucose and affect intestinal function (20). SCFAs regulate host metabolic health directly through a variety of mechanisms related to energy expenditure, appetite regulation, immune regulation, and glucose homeostasis, and its important functions are mainly in the maintenance of colonic epithelial energy supply, inhibition of pathogenic bacteria growth, regulation of the immune system and glucose and lipid metabolism (21). Bacillus, Clostridium and Bifidobacterium are the most frequent bacteria that produce SCFAs. Anaplasma is capable of producing acetate. Propionate is generated by a few dominating genera, including the basal species of mucinophilic Ackermannia, and it is also produced via the succinate route by the common and polymorphic Anaplasma Butyrate is generated by an anaerobic Clostridium species group. Butyrate, for example, has been shown to increase mitochondrial activity, prevent metabolic endotoxemia, inhibit the secretion of pro-inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), improve insulin sensitivity, has anti-inflammatory potential, and improves intestinal barrier function (22). Acetate can also be converted to cholesterol or fatty acids, and propionate can be involved in gluconeogenesis (23). By boosting protein kinase signaling in the liver and muscle, SCFAs can improve insulin sensitivity. Gprotein-coupledreceptor-41 (GPR-41) and GPR-43 are both found in human islets, where activation of GPR43 promotes insulin secretion and activation of GPR41 acts as an inhibitor, both of which work together to maintain insulin release order and glucose homeostasis (24). SCFAs can also stimulate insulin secretion by interacting with G protein-coupled receptors that enhance Glucagon-likepeptide-1 (GLP-1) and Peptide-YY (PYY) (25). SCFAs are not only metabolites of anti-inflammatory bacteria, but they also work as immune boosters, assisting the host in fighting inflammation. Increased levels of microbial gut-derived SCFAs are regarded to be favorable to health, while gut microbial imbalance caused by intestinal inflammation and decreased SCFAs may be connected to diabetes etiology (26). intestinal microbiota disruptions may alter the synthesis and metabolism of SCFAs in vivo, resulting in decreased insulin sensitivity and disrupted insulin secretion, leading to the development of T2DM.

Branched chain amino acids (BCAAs) are the basic amino acids that make up proteins, including leucine, isoleucine, and valine, and their levels in the blood alter insulin sensitivity. Horiuchi et al. (27) discovered that decreasing the protein content of mice’s food decreased insulin secretion, but increasing BCAAs in the diet restored insulin secretion and brought it back to normal levels. However, high doses of BCAAs may lead to insulin resistance. High levels of BCAAs can act as an upstream trophic signal by initiating the mTOR signal transduction pathway and inhibiting the expression of the translocator Kruppel-like factor 15 (KLF15), a key regulator of lipid, glucose, amino acid, and bile acid metabolism, resulting in increased insulin sensitivity and glycogen synthesis (28, 29). The synthesis of BCAAs in the body is intimately tied to intestinal microbiota, and the levels of BCAAs and their metabolites in the body also affect the flora (30, 31). As a result, gut flora can influence insulin sensitivity by influencing BCAAs levels, which play a vital part in the development of T2DM.

LPS, a major component of the cell wall of Gram-negative bacteria, causes an inflammatory response (32, 33). TLRs are natural immune system receptors that play a key role in triggering an inflammatory response. TLR4 and NF-κB play critical roles in the LPS-mediated signal transduction pathway (34). TLR4 receptors detect and bind LPS, which activates the NF-κB signal transduction pathway, causing the production of proinflammatory molecules such as IL-6 and TNF-α, causing inflammation and increasing insulin resistance. Intestinal microbiota alteration can result in the production of high amounts of LPS and inflammatory chemicals, leading in chronic and persistent inflammation, structural damage, malfunction, and even apoptosis of pancreatic-cells, Consequently, insufficient insulin secretion and insulin resistance occur, leading to the development of T2DM (35).

Bile acids (BAs) are an essential component of bile and the main result of cholesterol metabolic conversion in the liver. Bile acids have a vital role in intestinal absorption, transportation, and distribution of fat-soluble vitamins and lipids. It controls the network of metabolic signal transduction pathways involved in in the metabolism of glucose, lipid, drug, and energy, and facilitating lipid and fat-soluble vitamin absorption (36). Bile acid control necessitates the cooperation of the liver, the intestine, and gut bacteria. Cholesterol is processed by the liver to form primary BAs and by the action of intestinal microbiota to form secondary BAs. BAs function primarily as signaling molecules and ligands in glucose metabolism via the farne-soid X receptor (FXR) signal transduction pathway. Bile acids can activate G protein-coupled bile acid receptor 5 (TGR5) and FXR while also inhibiting gluconeogenic gene expression (37). FXR has been demonstrated to change the makeup of intestinal bacteria, boost bile acid production, and improve glucose tolerance in obese T2DM mice when the vertical trocar stomach is removed (37). TGR5 activation in intestinal L cells causes GLP-1 release, which increases insulin secretion, decreases glucagon secretion, improves liver and pancreatic function, and reduces insulin resistance and metabolic inflammation caused by a high fat diet (38). It is worth noting that the majority of the research on the aforementioned pathways has been done in rodent models. In contrast, there are differences in the composition and hydrophobicity of the bile acid metabolic pool between humans and rodents, which have a large impact on bile acid signaling properties.

While boosting metabolic activities in the body, intestinal microbiota also influences host physiological functions such as immune system and intestinal epithelial cell formation, pathogen defense, and tissue homeostasis maintenance. The mucosal barrier of the intestine is a complex system combining tissue, cellular, chemical, and immunological levels. The endocrine system of the intestine and the mucosa of the intestine have a “one loss, one gain” connection. The intestinal tract is an essential component of the human immune system, intestinal inflammation is closely related to the intestinal microflora and, some researches has linked immunological problems to insulin resistance and other pathological characteristics of T2DM (39, 40). Damage to the intestinal mucosa can allow germs and their toxins to enter the body’s important tissues and organs via the bloodstream, triggering a metabolic inflammatory response. T2DM is frequently accompanied with injury to the intestinal mucosa, and the inflammatory response may also play a role in the development of T2DM (40). Intestinal immune cells are mostly found in the connective tissue of the lamina propria of the gut mucosa, which serves as a medium for communication between intestinal bacteria and the host, and are constantly impacted by intestinal microecology. The intestinal barrier normally prevents the stimulation of the immune system by pathogenic microorganisms; however, in the case of intestinal epithelial cell breakdown, abnormal tight junctions, and increased intestinal permeability, enterobacteria, viruses, and their metabolites can penetrate deeply into the lamina propria via the epithelium, stimulating adaptive immune responses and causing the release of various inflammatory factors (41). Wu et al. (42) demonstrated the most substantial effect of LPS on intestinal mucosal immunity. Endotoxemia caused changes in the ratio of the number of various lymphocytes in rat intestinal tissues. The intestinal immune system and the intestinal mucosa have a very strong connection, indicating an interdependent relationship.

The large amount of inflammatory factors released by immune disorders activates inflammatory signaling pathways in the intestinal mucosa, resulting in abnormal cell function or apoptosis and necrosis, which increases LPS and inflammatory factor leakage into the bloodstream and triggers a systemic chronic inflammatory response (43). Furthermore, intestinal immunological inflammation can affect the release of intestinal endocrine hormones such as TNF-α, which can suppress GLP-1 secretion via a receptor-dependent route, causing irregularities in glucose metabolism in the body (43).

The key cell types involved in immunological control in the immune system include Gut-associated lymphoid tissue (GALT), T-lymphocytes, B-lymphocytes, Group 3 intrinsic lymphoid cells, macrophages, and dendritic cells (41). Pattern recognition receptors (PRRs) are a class of receptors associated with the immune recognition of viruses, bacteria, fungi, or parasites and are part of the host’s innate defense system (44). LPS and multiple PAMPs activate PRRs, which sense microbes and infection factors and signal defense responses. Four classes of PRRs including transmembrane proteins, such as C-type lectin receptors (CLRs) and TLRs; cytoplasmic proteins, such as NOD-like receptors (NODs) and retinoic acid inducible gene-like receptors (RLRs) have been found (45). TLRs are the most well researched PRRs, and their recognition activates genetic programs via post-transcriptional control of transcription factors and mRNAs (46). Different microbial components of pathogens can mediate different responses of TLRs. TLRs are present in immune cells and somatic cells such as intestinal epithelial cells (47). TLR2 detects bacterial lipoproteins, whereas TLR4 recognizes bacterial LPS (as shown in Figure 2 ) (48). Their activation causes antigen-presenting cells to become activated, therefore combining with the autoimmune response and triggering signaling cascades in anticipation of protect against microbial invaders or heal injured tissues. Although this inflammatory reaction is necessary for eradication of infection, overactivity of TLRs can disturb immunological homeostasis, and persistent production of chemokines and pro-inflammatory cytokines may increase the likelihood of inflammation and immune disease (49, 50). Chassaing et al. (51) found that TLR5 is activated by bacterial flagellin, and mice lacking TLR5 develop colitis or metabolic syndrome, which is due to changes in the intestinal microbiota. This means that altered microflora leading to inflammatory responses can interfere with the expression of PRRs.

Furthermore, multiple studies have revealed that commensal bacteria’s metabolic byproducts, such as SCFAs, influence the immunological response of gut-associated lymphoid tissues (GALTs) via epigenetic processes, operating through self-defense and the immune evasion by commensal bacteria (41).

Diabetes mellitus is classified as Xiaokezheng in TCM, and its etiology is mostly owing to a lack of yin and fluids, as well as a predominance of dryness and heat. Diabetes mellitus is intimately linked to intestinal microbiota abnormalities in the body, according to Chinese medicine; however, intestinal microbiota disorders and spleen malfunctions are mutually causative. According to certain research, the status of normal intestinal microbiota is directly associated to the spleen (58). The ancient people believed that the spleen and stomach were the foundations of human survival, and that the spleen and stomach modified the body’s qi, blood, and vitality through eating. so the normal operation of the spleen and stomach is critical in the balance of intestinal microbiota. Bifidobacteria, Lactobacilli, and other beneficial bacteria in the intestinal tract, which can decompose food residues, metabolize them in the body in various ways, and finally transform them into essential substances to maintain body nutrition, allowing the human intestinal tract to remain balanced and healthy. Thus, managing intestinal microbiota can enhance spleen and stomach function, repair and ameliorate intestinal mucosal damage, restore intestinal wall permeability, regulate and translocate harmful bacteria in the intestinal tract, and enhancement of autoimmunity, all of which are important in combating of T2DM (59).

In recent years, many traditional Chinese herbs have been tried in combating of T2DM (60), and Astragali Radix can treat thirst primarily by “inducing clear qi to reach the lungs, harmonizing with the inhaled qi and transforming it into water, encouraging the upward movement of fluid in the stomach, and regulating the qi of the lower jiao.” Astragali Radix is thought to be a natural hypoglycemic agent with broad application potential is critical in combating of diabetes (61). Astragali Radix is a somewhat warm, sweet-tasting herb that belongs to the spleen and lung meridians and has a variety of actions include helping the body, tonifying qi and elevating yang, stimulating water retention, lowering swelling, and discharging pus and supporting sores (61). Polysaccharides, saponins, flavonoids, and other multi-class active components in Astragali Radix have strong preventative and therapeutic benefits on T2DM, including reducing insulin resistance, enhancing insulin sensitivity, antioxidant, and anti-inflammatory properties (61). By controlling intestinal microbiota abnormalities, increasing the immunological barrier function of intestinal mucosa, improving the body’s immunity, and regulating metabolites, Astragali Radix can exhibit anti-diabetic actions (61). In terms of pharmacological mechanism, Astragali Radix can increase tyrosine kinase activity, improve insulin signal transmission, and aid in combating of diabetes and its complications (61). Wang et al. (61) Astragali Radix adjusts the ratio of SCFAs-producing bacteria such as Flavonifractor_and Alloprevotella and inflammation-associated bacteria such as Alistipes and Deferribacteres. Li et al. (11) used 16S rRNA sequence determination to examine the effects of Astragali Radix on the regulation of intestinal microbiota in type 2 diabetic mice and discovered that Astragali Radix significantly improved the diversity and abundance of intestinal microbiota from diabetic mice, inducing an improving in the abundance of Bifidobacterium and Lactobacillus, thereby controlling body weight and blood glucose in type 2 diabetes mice.

Astragali Radix as the main herb, together with various other herbal formulas, has also shown remarkable results in diabetes control through acting on the intestinal microbiota (as shown in Table 2 ). Cao et al. (62) evaluated the safety and efficacy of the new formula Qi-Jian combination (QJ) (Astragali Radix, Yang Mei, Ge Gen, and Huang Lian) in combating of type 2 diabetes by metabolomics, and showed that it can regulating blood glucose and triglyceride (TC) levels, reducing liver and kidney damage, and increasing production of SCFAs and decreasing production of BCAAs. PCoA analysis of intestinal microbiota indicated that QJ therapy significantly increased the number of Akkermansia and Bacteroidetes, reduced the number of Firmicutes (62). The system pharmacology paradigm also demonstrated that QJ worked via the PPARA, AKT1, and TP53 proteins (62). It was determined that QJ significantly reduced T2DM, and this impact was associated with changed metabolite profiles and intestinal microbiota. Xie et al. (63) showed by 16S rRNA sequence determination that the various ameliorative effects of Pi-Dan-Jian-Qing decoction (PDJQ) (Pseudostellaria heterophylla, Astragali Radix, Rhizoma atractylodes, Radix scrophulariae, Puerariae lobatae radix, Scutellaria, Coptis chinensis, Salvia miltiorrhiza, dried ginger) on T2DM, including improving hyperglycemia, hyperlipidemia and insulin resistance, improving liver and kidney function and regulating inflammatory response and oxidative stress. The mechanism of PDJQ for T2DM may be related to the improvement of intestinal microflora dysbiosis, regulation of tryptophan and histamine metabolism and citric acid cycle. The mechanisms of on T2DM are likely linked to an improvement in the dysbiosis of intestinal microbiota and modulation of tryptophan metabolism, histamine metabolism, and the TCA cycle. In addition, ELISA results showed that PDJQ decreased the levels of TNF-α, IL-1β and IL-6. PDJQ can improve the clinical symptoms of spleen deficiency and dampness-heat caused by T2DM, and can reduce both postprandial blood glucose (PBG) and fasting blood glucose (FBG) (64). The Jin-Xiao-Xiao-Ke decoction (JXXKD), first reported in Wai Tai Mi Yao Fang which was writing by Wang Tao during the Tang Dynasty (AD 752), is a traditional prescription used to treat symptoms “Xiao Ke,” which is known as T2DM in modern medicine. This prescription was used to cure “Xiao Ke” and considerably reduce symptoms like polyuria and thirst. Animal studies revealed that JXXKD dramatically reduced polyuria symptoms, lowered FBG protein levels, and improved liver fat deposition in diabetic rats (65). Guo et al. (66) mentioned in their study about the mechanism of treatment of T2DM that Drug Pair of Astragali Radix and Dioscoreae Rhizoma modulates the metabolism of BCAAs (e.g., leucine and isoleucine) and SCFAs (e.g., butyric acid and propionic acid) in vivo. low-density lipoprotein (LDL), total cholesterol (TC) and Lipid levels were reduced and high-density lipoprotein (HDL) levels were increased in T2DM rats after these treatments. In addition to this, they found that Drug Pair of Astragali Radix and Dioscoreae Rhizoma can regulate the disturbance of energy metabolism and reducing insulin resistance.

Astragaloside (AS), one of the main active ingredients of Astragali Radix, which chemical nature is a kind of cycloartane-type triterpene glycoside chemical. Recent studies have shown that AS has hypoglycemic effects and may alleviate diabetic complications through several potential molecular mechanisms. Gong et al. (67) reported that AS significantly lowered blood lipid, glucose, insulin resistance, and oxidative stress levels, In T2DM rats. According to histology results, AS has a role in protecting the cellular integrity of the pancreas and liver. AS modulates the type and number of intestinal microbiota and increases butyric acid levels in diabetic mice (67). AS treatment of diabetes was found to be achieved by modulating two signaling pathways, PI3K/AKT and AMPK/SIRT1, and confirmed using insulin-resistant HepG2 cells and inhibitors (67). Cheng et al. (68) discovered that AS-IV can participate in the elevation of glucocorticoid expression in rats. Lv et al. (69) reported that the amount of glucose-6-phosphatases and glycogen phosphatases in the liver was lowered in mice with T2DM treated with AS-IV, leading to alleviation of insulin resistance and decreases in blood glucose and TC levels. He & Gong et al. (67, 70) also reported that Astragaloside IV may promoting butyric acid production by modulating the intestinal microbiota profile. Zhang et al. (71) discovered that AS-IV administration might ameliorate metabolic syndrome induced by high fructose diet in rats, resulting in lower blood pressure and improved insulin resistance. Qi et al. (72) showed that AS-IV can alleviate the Glycated albumin causes epithelial-mesenchymal transition (EMT) in the cell of Normal Rat Kidney-52E line via redox balance modulation. Similarly, He et al. (73) found that AS-IV protected rat kidney from hyperinsulinemia. The mechanisms were inhibition of TNF-α and IL-1 overproduction, reduction of oxidative stress, enhancement of transient receptor potential channel (TRPC6) expression, and inhibition of extracellular-signal-regulated kinase 1/2 (ERK1/2) activation. AS-IV reduces Diabetes-induced nephropathy by ameliorating oxidative stress and suppressing the expression of inflammatory genes driven by NF-κB in human mesangial cells (74, 75).

Like Saponins, Astragalus polysaccharides (APS) are one of the main active components of Astragali Radix. It is very closely related to intestinal microbiota. APS has a positive regulatory effect on intestinal microbiota, reduces insulin resistance and improves islet secretory cells in T2DM. It has been shown that after gavage of APS in db/db diabetic mice, the specific value of the phylum Bacteroides and Thick-walled Bacteroides in the organism was increased significantly, and the abundance of Lactobacillus and Sartorius increased, while Spirochaete mucocephalus and Treponema were growth inhibited, confirming that APS can delay glucose diffusion, treat diabetes and repair its tissue damage (76). APS not only has a positive regulatory effect on intestinal microbiota disorders, but also regulates body metabolism, improves the intestinal milieu, and plays a vital role in a wide range of properties as an example anti-inflammatory, immunomodulatory and anti-diabetic properties (77). Ming et al. (78) found that APS significantly increased serum concentrations of SCFAs, including butyric and propionic acids, by increasing the abundance of SCFA-producing genera such as Akkermansia, Coprococcus, and Oscillospira in the intestine. APS may control immune function by boosting cytokine release, promoting immune cell proliferation, and influencing immunoglobulin (Ig) production and immunological signaling (79). APS decreased oxidative stress and inflammation levels, alleviated Glucose and lipid metabolism abnormalities, and avoided organ destruction in T2DM mice, according to Chen et al. (80), the APS might preserve the intestinal barrier by reducing oxidative stress and intestinal inflammation stress, as well as inhibiting the pathogenic bacteria Shigella and promoting the development of good bacteria Allobaculum and Lactobacillus. Antibiotic test have shown that the possible glucose-lowering mechanism of APS is the restoration of the intestinal barrier by altering particular intestinal bacteria.

The pathophysiology of T2DM is mostly related to insulin resistance, islet β cell dysfunction, and insulin insufficiency. Tanase et al. (81) found that normal islet β cell actions include decreasing insulin resistance, regulating lipid metabolism, boosting insulin production, and lowering blood glucose levels. Wang et al. (82) showed through their study that APS may lower blood glucose and enhance insulin sensitivity by lowering endoplasmic reticulum stress in T2DM patients. Its method may entail decreasing ATF6 activation (caused by endoplasmic reticulum stress), reversing ATF6 translocation in cells, and inhibiting the high expression of a certain protein phosphatase. The above changes reduce the stress on the liver endoplasmic reticulum, which enhances insulin sensitivity (82). Furthermore, Wei et al. (83) found that APS can decreasing T2DM insulin resistance by maintaining or increasing miRNA-203a-3p expression, lowering the glucose-regulated protein (GRP78) expression, and modulating the endoplasmic reticulum stress-related signaling pathway protein expression. According to Seino et al. (84), APS can promotes anaerobic oxidation in muscle tissue and attenuates insulin resistance. APS has also been found in several studies to stimulate cell differentiation and induce the secretion of adiponectin, increases T2DM rat glucose transporter 4 (GLUT4) expression in adipocytes and AMPK expression in liver tissue, downregulations resistin protein and mRNA in adipocytes (85–87). Another report said that APS can improve the condition of type 2 diabetic rats by modulating the intestine-pancreatic axis and related signaling pathways (88).

Collectively, the primary impact of APS on diabetes is a decrease in insulin resistance, encouragement of islet cell proliferation, and suppression of islet β cell death. Its pharmacological impact is primarily mediated through altering the expression of associated genes and proteins (86). The growth environment of intestinal microorganisms has a high correlation with the function of the spleen and stomach. The above studies suggest that APS has various effects on anti-inflammation, promotion of ulcer tissue proliferation and repair of damaged blood vessels from the perspective of the spleen. APS plays a crucial role in the treatment and improvement of diabetes and associated disorders by regulating the microecological environment in vivo.

Astragali Radix membranaceus contains flavonoids, which have been shown in recent studies to have immune-boosting, anti-inflammatory, glucose metabolism-regulating, and diabetes progression-controlling properties. According to Zhang et al. (89), a flavonoid component of Astragali Radix may effectively treat diabetic kidney damage in db/db mice by inhibiting IB and NF-B p65 and decreasing inflammatory markers in blood. Furthermore, after treatment of this component, blood glucose levels dropped in db/db obese mice, which is assumed to be connected to the anti-inflammatory impact. In mice treated with this component, serum TC levels were lowered, and glucose intolerance and insulin resistance were regulated (90). After oral administration of flavones from Astragali Radix chemistry, enriching the intestinal microbiota in STZ/high-fat diet-induced diabetic mice, flavones from Astragali Radix were shown to lower fasting blood glucose and food intake (90). In vitro experiments revealed that Astragali Radix flavonoids boosted HT22 cell survival and preserved the Normalization of the intestinal barrier function in the CaCO₂ monocyte layer, a mechanism involving the PGC1/AMPK pathway (91). Flavones from Astragali Radix significantly reduced cholesterol and cholesteryl esters, TC, glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and LDL levels while elevating HDL levels in both in vivo and in vitro experiments. Cholesterol 7α-hydroxylase (CYP7A1) and glucose transporter 2 (GLUT2) expressions were increased significantly in the treatment of flavones from Astragali Radix, and TGR5 and FXR played key roles in regulating lipid and bile acid metabolism (92).