Use of albiflorin for preventing and treating depression comorbid with metabolic syndrome and depression comorbid with type ii diabetes

Abstract

The use of albiflorin in the preparation of a drug, health food, dietary supplement or functional soft candy for treating depression comorbid with metabolic syndrome and depression comorbid with type II diabetes. Albiflorin prevents and treats depression comorbid with metabolic syndrome (Mets) by means of multiple mechanisms including correcting stress-induced metabolic abnormalities, ameliorating intestinal flora dysbiosis in depression, improving the metabolic function of intestinal flora, reducing the abundance of Prevotella, lowering the ratio (B / F) of Bacteroidetes (B) to Firmicute (F), inhibiting the overactivation of IDO1 (indoleamine 2,3-dioxygenase 1), promoting the function of an endogenous melatonin system, restoring the normal circadian rhythm, and increasing the secretion of bile acids, amino acids and vitamins in the human body.

Description

Uses of paeoniflorin in the prevention and treatment of metabolic syndrome and type 2 diabetes mellitus comorbid with depression. Technical Field

[0001] This invention belongs to the field of biomedicine and relates to the use of paeoniflorin in preventing and treating metabolic syndrome (Mets) comorbid with depression by correcting stress-induced metabolic abnormalities and improving gut microbiota balance. SSRIs such as fluoxetine may further induce metabolic disorders and gut microbiota imbalance after administration. Therefore, in terms of efficacy evaluation in preventing and treating metabolic syndrome (Mets) comorbid with depression, paeoniflorin has a significant advantage over SSRIs such as fluoxetine. Background Technology

[0002] Metabolic syndrome (Mets) is a group of metabolic disorders including central obesity, dyslipidemia, hypertension, hyperglycemia, and cardiovascular disease. It can increase the incidence and mortality risk of cardiovascular disease (CVD), worsen psychiatric symptoms, impair cognitive function, and increase the likelihood of relapse into depression. Depression often co-occurs with metabolic syndrome (Mets). For example, the prevalence of type 2 diabetes mellitus (T2DM) complicated by depression in China is as high as 30.98%. Furthermore, existing antidepressants may induce or enhance metabolic syndrome during treatment (drug-induced Mets), complicating the patient's condition, making it more complex and dangerous, thereby increasing medical expenses and harming the patient's physical and mental health.

[0003] Most existing antidepressants (such as the SSRI fluoxetine) carry a risk of inducing or increasing drug-induced metabolic syndrome (Mets) associated with depression. The potential risk of developing drug-induced metabolic syndrome (Mets) in patients with depression after long-term use of antidepressants, which is harmful to human health, has increasingly attracted extreme attention from the global pharmaceutical community.

[0004] In 2008, researchers from Harvard Medical School conducted a nearly 10-year follow-up study of 120,000 patients treated at Massachusetts General Hospital between 1996 and 2005. The study found that patients using antidepressants had a 46% higher risk of developing diabetes than those not using antidepressants. The highest risk was observed in women using SSRIs (such as fluoxetine) (JAMA, IF: 72.40). This finding raised global concerns about the safety risks of antidepressants, suggesting that physicians need to carefully consider potential factors that could induce diabetes (metabolic syndrome) in patients when using antidepressants.

[0005] A 2012 study by a research team at Oxford University in the UK, analyzing 33 cohort and case-control studies involving over 2 million participants, found that patients using antidepressants had a 30% higher risk of developing diabetes than those not using antidepressants. The highest risk was observed in patients using SSRIs (such as fluoxetine) (British Medical Journal IF: 69.20). This study further suggests that antidepressants may be a potential risk factor for the comorbid diabetes (metabolic syndrome) associated with depression.

[0006] In 2024, Dr. Andres Catala-Lopez of King's College London published a paper titled "Antidepressants and the Risk of Metabolic Syndrome: A Meta-analysis of Observational Studies" in *The Lancet Diabetes & Endocrinology* (IF: 44.86). This study involved 1,958,523 participants and 101,474 cases of metabolic syndrome, encompassing 12 types of antidepressants (tricyclic, tetracyclic, TCAs, SSRIs, SNRIs, etc.) and analyzing 28 observational studies. The study found that patients using antidepressants had a 17% increased risk of developing metabolic syndrome compared to those not using them. Therefore, antidepressant use is associated with an increased risk of metabolic syndrome, and clinicians should consider the patient's metabolic status and implement appropriate monitoring and intervention measures when choosing antidepressant treatment.

[0007] A groundbreaking paper in *Science* (IF: 63.71) has revealed that "gut microbiota-host isoenzyme analysis reveals gut microbiota-derived DPP-4 as a novel antidiabetic target." The paper discloses that various Bacteroides in the gut possess DPP-4 (dipeptidyl peptidase) activity, which triggers type 2 diabetes by inhibiting GLP-1. DPP-4 inhibitors (such as sitagliptin) have almost no effect on gut microbiota-derived DPP-4. Furthermore, the negative effects of existing antidepressants on the gut microbiota of patients (e.g., increasing Bacteroides abundance) may increase the risk of comorbid diabetes in patients with depression.

[0008] A survey by the Chinese Diabetes Society of the Chinese Medical Association shows that the prevalence of metabolic syndrome (Mets) among urban residents aged 20 and above in China is 14% to 16%, meaning that one in every six to seven people is a patient. A significant portion of these patients develop drug-induced Mets due to the use of antidepressants. Therefore, the development of a new generation of antidepressants that can prevent and treat Mets comorbidities is urgently needed.

[0009] Summary of the Invention

[0010] The purpose of this invention is to address the technical problem that existing antidepressants in the treatment of depression carry the risk of inducing or increasing metabolic syndrome comorbid with depression (Mets). This invention provides the application of paeoniflorin in the preparation of drugs for treating metabolic syndrome comorbid with depression and type 2 diabetes comorbid with depression. By regulating the serotonin metabolic pathway (upregulating serotonin metabolism / inhibiting kynurenine metabolism) and improving abnormal gut microbiota, this invention prevents and treats metabolic syndrome comorbid with depression (Mets), representing a novel application of paeoniflorin in this invention.

[0011] To achieve the above objectives, the present invention provides the application of paeoniflorin and white peony extract in the preparation of drugs, health foods, dietary supplements, and functional gummies for the prevention and / or treatment of metabolic syndrome comorbid with depression, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

[0012] In particular, the aforementioned metabolic syndrome (Mets) comorbid with depression includes conditions such as obesity, central obesity (abdominal obesity), hyperlipidemia, hypertension, hyperglycemia, energy metabolism disorders, and cardiovascular disease.

[0013] Metabolic syndrome increases the risk of cardiovascular disease (CVD) and death, worsens psychiatric symptoms, impairs cognitive function, and increases the risk of relapse into depression.

[0014] In particular, comorbidity (also known as co-occurrence or combined illness) refers to the coexistence of two diseases. For example, comorbidity of anxiety and depression refers to the simultaneous presence of anxiety and depressive symptoms, where both groups of symptoms meet their respective diagnostic criteria if considered separately.

[0015] In another aspect, the present invention provides a combination drug of paeoniflorin or white peony extract with monoamine antidepressants such as SSRIs, which enhances the antidepressant effect and reduces the risk of drug-induced metabolic syndrome (Mets) induced by monoamine antidepressants such as SSRIs, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

[0016] One aspect of the present invention provides the use of paeoniflorin and white peony extract in the prevention and / or treatment of type 2 diabetes; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression induced by enterobiotic DPP-4; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression induced by IDO1 overactivation, wherein the white peony extract is paeoniflorin containing a therapeutic amount.

[0017] In another aspect, the present invention provides a combination drug of paeoniflorin or white peony extract with human-derived DPP-4 inhibitors such as sitagliptin, which enhances the efficacy against type 2 diabetes mellitus comorbid with depression induced by enterobiotic DPP-4 or IDO1 overactivation, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

[0018] In another aspect, the present invention provides a combination drug of paeoniflorin or white peony extract and statins, which enhances efficacy and reduces side effects, synergistically prevents and treats cardiovascular diseases comorbid with depression, and reduces the risk of type 2 diabetes induced by statins, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

[0019] Another aspect of the present invention provides the application of paeoniflorin and white peony extract in the preparation of drugs, health foods, dietary supplements, and functional gummies for treating type 2 diabetes mellitus comorbid with depression, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

[0020] In particular, the type 2 diabetes comorbid with depression is type 2 diabetes with gut microbiota-derived DPP4 induced by abnormally increased abundance of Bacteroides due to gut microbiota dysbiosis caused by treatment for depression.

[0021] In particular, the aforementioned type 2 diabetes comorbid with depression is either type 2 diabetes comorbid with depression induced by enterobiotic DPP-4 or type 2 diabetes comorbid with depression induced by IDO1.

[0022] In another aspect, the present invention provides the use of a paeoniflorin composition in the preparation of a treatment for type 2 diabetes comorbid with depressive disorder, wherein the paeoniflorin composition is a combination of paeoniflorin and a DPP-4 inhibitor.

[0023] In particular, the DPP-4 inhibitor mentioned is sitagliptin.

[0024] In another aspect, the present invention provides the use of a paeoniflorin composition in the preparation of a treatment for cardiovascular diseases comorbid with depressive disorders, wherein the paeoniflorin composition is a combination of paeoniflorin and statins.

[0025] In particular, the statin mentioned is atorvastatin.

[0026] In particular, paeoniflorin, or white peony extract containing therapeutic doses of paeoniflorin, can be used in combination with statins to enhance efficacy and reduce side effects, synergistically preventing cardiovascular diseases comorbid with depression and avoiding the risk of inducing type 2 diabetes.

[0027] The combination of paeoniflorin and statins reduces the side effects of statins inducing diabetes (statins exacerbate insulin resistance by lowering GLP-1 levels in a microbial-dependent manner).

[0028] This invention utilizes metabolomics, 16S rDNA sequencing, and other methods to explore the pathogenesis, biological targets, and precision treatment of metabolic syndrome (Mets) comorbid with depression:

[0029] Firstly, depression or its treatment can induce or increase the risk of metabolic syndrome in the following ways:

[0030] I. Tryptophan metabolism disorder: IDO (indoleamine 2,3-dioxygenase) is activated, leading to the conversion of more tryptophan to quinolinic acid via kynurenine (Kyn), resulting in a decrease in serotonin (5-HT). 5-HT deficiency is one of the main pathogenic mechanisms of depression. Kynurenine (Kyn) stimulates AhR (aromatic hydrocarbon receptor) expression, activating the AhR / Stat3 / IL-6 signaling in adipocytes, disrupting lipid homeostasis and insulin sensitivity, thereby mediating obesity and insulin resistance. In patients with metabolic syndrome, serum IDO1 expression levels are typically elevated, leading to an imbalance in tryptophan metabolism, subsequently affecting insulin sensitivity and lipid metabolism disorders, inducing diabetes. IDO1 can also promote the development of atherosclerosis by affecting inflammatory responses, increasing the risk of cardiovascular disease. (From the paper "Indoleamine 2,3-dioxygenase 1 promotes β-cell dysfunction and diabetes in mice," published in *Cell Metabolism* (IF: 31.90) in June 2023).

[0031] Second, depression disrupts the metabolic balance of gut microbiota, leading to a decrease in bile acid secretion from the liver. This induces changes in the permeability of intestinal epithelial cells, increasing the reabsorption of bile acids. Bile acids can promote the digestion and absorption of fats and can induce the secretion of glucagon-like peptide-1 (GLP-1), increasing insulin sensitivity. Therefore, depression leading to a decrease in bile acid secretion can induce metabolic syndrome (Mets), thereby affecting fat metabolism and energy metabolism, and increasing the risk of obesity, dyslipidemia, hypertension, and hyperglycemia.

[0032] III. Depression affects the normal distribution of gut microbiota, causing intestinal microecological imbalance, with the following prominent manifestations: 1. Increased abundance of Bacteroides (↑), decreased abundance of Firmicutes (↓), and an increased Bacteroides / Firmwallis (B / F) ratio (↑); increased Bacteroides abundance and Bacteroides / Firmwallis (B / F) ratio promote the secretion of enterogenic DPP-4, inhibit GLP-1 activity, and increase the risk of inducing type 2 diabetes. 2. A significant increase in Prevotella (Bacteroides) in the gut. The increase in Prevotella abundance causes an imbalance in the body's energy metabolism, not only inducing obesity, but also being significantly associated with increased BMI, insulin resistance, hypertension, and non-alcoholic fatty liver disease in non-diabetic patients.

[0033] Because depression is often accompanied by metabolic syndrome (Mets), psychiatrists must closely monitor patients' metabolism when treating depression with medication, and take early preventative measures against any possible Mets.

[0034] This invention, through comparative research, found that SSRIs such as fluoxetine increase the risk of developing metabolic syndrome (Mets) comorbid with depression; paeoniflorin, however, addresses this shortcoming, preventing Mets from developing. The specific effects and uses of paeoniflorin are as follows:

[0035] I. Paeoniflorin inhibits IDO overactivation and prevents Mets-related depression.

[0036] IDO is a tryptophan-degrading enzyme that cleaves the indole ring of tryptophan, metabolizing it into kynurenine (Kyn). Overactivation of IDO can lead to tryptophan depletion, inducing depression and metabolic syndrome (Mets).

[0037] While existing mainstream antidepressants such as fluoxetine and other 5-HT reuptake inhibitors (SSRIs) work by inhibiting 5-HT reuptake at neural synapses, they also promote the activity of IDO enzymes in the tryptophan metabolic pathway, increasing the risk of inducing metabolic syndrome (Mets).

[0038] The paeoniflorin glycoside of this invention increases the content of serotonin in the brain by inhibiting the overactivation (↓) of IDO in the tryptophan metabolic pathway. It not only has antidepressant effects, but also promotes insulin secretion by improving lipid metabolism, thus preventing and treating metabolic syndrome (Mets) comorbid with depression.

[0039] This invention uses D-serine (D-Ser) as a substrate probe and applies the known DAAO inhibitor AS057278 to verify the roles of benzoic acid and paeoniflorin in a DAAO enzyme culture system. Metabolites in ICR mouse feces were identified using LC / MSn-IT-TOF. The relationship between the antidepressant activity of paeoniflorin and the gut microbiota, as well as the concentration of benzoic acid in the brain, was investigated. It was found that benzoic acid, a metabolite of paeoniflorin, is an inhibitor of D-amino acid oxidase (DAAO). It can inhibit DAAO to prevent the degradation of D-serine (D-Ser) and promote NMDA receptor activity, thus exerting an antidepressant effect (as shown in the paper "Study on the mechanism of action of paeoniflorin in antidepressant action by regulating gut-brain axis metabolic pathways" published in Theranostics in August 2018). Benzoic acid can also reduce serum hydroxypyruvate (HPA) levels by inhibiting DAAO, restoring insulin function and controlling blood glucose, thus treating type 2 diabetes mellitus (T2DM), a comorbidity of depression.

[0040] In addition, the paeoniflorin glycoside of the present invention can also promote the function of the endogenous melatonin system, improve sleep quality by improving circadian rhythm, and prevent Mets (lowering blood pressure, blood lipids, and reducing weight).

[0041] Fluoxetine has the opposite effect, inhibiting melatonin secretion, disrupting circadian rhythms, and further aggravating sleep disorders and metabolic dysfunction in patients with depression.

[0042] II. Preventing Mets by improving gut microbiota metabolism and increasing bile acid secretion

[0043] VIP analysis of the effects of paeoniflorin on the gut microbiota of CUMS rats revealed that, compared with the depression group, administration of paeoniflorin increased bile acid levels, and significantly increased amino acid and vitamin levels, indicating that the gut microbiota function of CUMS rats was improved, and some functions had returned to normal. Paeoniflorin can improve gut microbiota metabolism, promote bile acid secretion, and prevent Mets. Fluoxetine has the opposite effect, further exacerbating the gut microbiota metabolic disorder in patients with depression.

[0044] A comparative analysis of gut microbiota metabolism in rats in the VIP group (blank control group), the depression group (CUMS group), and the fluoxetine group revealed that fluoxetine administration severely inhibited gut microbiota metabolism. The levels of all 25 (100%) most significantly different metabolites (including bile acids) in rat feces were significantly lower in the fluoxetine group than in the depression model group. This suggests that fluoxetine treatment exacerbates gut microbiota dysbiosis, inhibits bile acid secretion, disrupts the bile acid's function in improving gut microbiota metabolism, and increases the incidence of Mets (consistent with clinical results).

[0045] III. Preventing Mets by Restoring the Gut Microbiota Balance in Depression

[0046] This invention utilizes 16S rDNA expression to compare and detect the effects on fecal flora in rats of the normal group, the depression group (CUMS), the paeoniflorin group, and the fluoxetine group, and found that:

[0047] 1. In the fecal microbiota of CUMS group rats, the relative abundance of Prevotella was significantly higher than that of the normal group, indicating that chronic stress can cause disorders in fat metabolism and glucose metabolism in rats. Paeoniflorin group significantly reduced the relative abundance of Prevotella (P<0.01), preventing Mets by restoring the balance of gut microbiota in depression. Fluoxetine group had the opposite effect, increasing the abundance of Prevotella (Prevotella affects the body's normal energy metabolism, causing energy metabolism imbalance, weight gain, and obesity).

[0048] The use of paeoniflorin in the prevention and treatment of metabolic syndrome comorbid with depression of the present invention has antidepressant function and can also prevent and treat Mets. Paeoniflorin is superior to SSRIs.

[0049] 2. Bacteroides (B) and Firmicutes (F) are the main components of the gut microbiota. Changes in the B / F ratio are a key indicator of gut microbiota dysbiosis and a sign of metabolic disorders leading to Mets. Compared with the normal control group, the B / F ratio in the feces of rats in the depression model group was significantly increased (↑), indicating that CUMS disrupted the balance of the gut microbiota. After administration of paeoniflorin, the B / F ratio decreased significantly compared with CUMS (↓), indicating that paeoniflorin alleviated the CUMS-induced gut microbiota dysbiosis in rats and prevented the occurrence and development of Mets. Fluoxetine not only lacks this function, but also further aggravates gut microbiota dysbiosis and increases the risk of metabolic syndrome (Mets).

[0050] This invention discloses another use of paeoniflorin: the treatment of type 2 diabetes comorbid with depression. When paeoniflorin is used in combination with the DPP-4 inhibitor sitagliptin, it can improve gut microbiota, inhibit the abundance of Bacteroides, reduce gut-derived DPP-4, and enhance the efficacy of sitagliptin, thereby treating type 2 diabetes induced by gut-derived DPP-4.

[0051] This invention relates to a combination of paeoniflorin and the DPP-4 inhibitor sitagliptin. By improving the intestinal flora, inhibiting the abundance of Bacteroides, reducing intestinal DPP-4, and enhancing the efficacy of sitagliptin, this combination is used to treat type 2 diabetes induced by intestinal DPP-4. Furthermore, experiments have demonstrated that paeoniflorin also has a strong inhibitory effect on human DPP-4, and its metabolite benzoic acid can restore pancreatic function and control blood glucose by inhibiting serum HPA levels. Therefore, paeoniflorin can serve as a direct synergist for hypoglycemic drugs such as sitagliptin.

[0052] This invention relates to paeoniflorin or a white peony extract containing a therapeutic dose of paeoniflorin for the preparation of drugs, health foods, and dietary supplements for the prevention and treatment of metabolic syndrome (Mets) comorbid with depression; or to combining it with SSRIs such as fluoxetine to increase antidepressant efficacy and reduce the risk of inducing Mets; or to combining it with DPP-4 inhibitors such as sitagliptin to enhance the treatment of type 2 diabetes comorbid with depressive disorders; or to combining it with statins to treat cardiovascular diseases, enhancing efficacy and reducing side effects, and lowering the risk of inducing diabetes.

[0053] Compared with the prior art, the present invention has the following advantages:

[0054] This invention relates to paeoniflorin lactone, which improves the ecological imbalance of gut microbiota in depression by correcting stress-induced metabolic abnormalities, enhancing the metabolic function of gut microbiota, reducing the abundance of Prevotella, decreasing the Bacteroides (B) to Firmicutes (F) ratio (B / F), inhibiting the overactivation of IDO1 (indoleamine 2,3-dioxygenase 1), promoting the function of the endogenous melatonin system, restoring normal circadian rhythm, and increasing the secretion of bile acids, amino acids and vitamins in the human body, thus preventing and treating metabolic syndrome (Mets) comorbid with depression through multiple mechanisms.

[0055] This invention relates to paeoniflorin or a white peony extract containing a therapeutic dose of paeoniflorin, for the preparation of drugs, health foods, and dietary supplements for the prevention and treatment of metabolic syndrome comorbid with depression (Mets) and type 2 diabetes comorbid with depression; or paeoniflorin can be used in combination with SSRIs such as fluoxetine to increase antidepressant efficacy and reduce the risk of inducing Mets; or in combination with DPP-4 inhibitors such as sitagliptin to enhance the treatment of type 2 diabetes comorbid with depressive disorders; or in combination with statins to treat cardiovascular diseases, enhancing efficacy and reducing side effects, and lowering the risk of inducing diabetes.

[0056] The present invention relates to paeoniflorin, or a white peony extract containing a therapeutic dose of paeoniflorin, which can be used in combination with monoamine antidepressants such as SSRIs to enhance antidepressant efficacy and reduce the risk of inducing metabolic syndrome (Mets) as a comorbid comorbidity of depression. Attached Figure Description

[0057] Figure 1 is a metabolic schematic diagram showing how paeoniflorin improves depression and prevents metabolic syndrome by downregulating the kynurenic acid metabolic pathway and upregulating the serotonin metabolic pathway.

[0058] Figure 2 shows the effect of paeoniflorin on IDO protein expression in the hippocampus of CUMS rats. # indicates an increase compared with the CUMS group (P<0.05); ## indicates a significant increase compared with the CUMS group (P<0.01); ** indicates a significant decrease compared with the CUMS group (P<0.01).

[0059] Figure 3 shows the circadian rhythm-related metabolites in rat hippocampus regulated by paeoniflorin.

[0060] Figure 4 shows the effect of paeoniflorin on the expression of melatonin receptor 1 (MT1) protein in the hippocampus of CUMS rats. ## indicates a significant increase compared with CUMS (P<0.01); ** indicates a significant decrease compared with CUMS (P<0.01).

[0061] Figure 5 shows that PLS-DA analysis indicates a significant difference in gut microbiota metabolism between the CUMS group rats and the normal control group, and that paeoniflorin administration helps restore normal gut microbiota metabolism.

[0062] Figure 6 shows that PLS-DA analysis indicates that fluoxetine causes the gut microbiota metabolism in rats to deviate more from the normal control group (more deviating from the normal state).

[0063] Figure 7 shows the VIP analysis of gut microbiota metabolism in rats of the CUMS group and the normal control group (Top 20 metabolites, VIP>1.5 indicates significant difference).

[0064] The figure shows the top 20 compounds with significant differences in gut microbiota metabolism between the normal control group and the CUMS group rats, listed in descending order of significance: p-Aminohippuric acid; Pyridoxal; PE (36:3); Cholic acid; Pyroglutamic acid; Glycocholic acid; Chenodeoxyglycocholic acid; Choline; L-Tyrosine; Dimethylglycine; Citrulline; Octadecanoylcarnitine; Suberic acid; L-Glutamic acid; acid: L-glutamic acid; Methylcysteine: acetylcysteine ​​methyl ester; Adenosine: adenosine; 9-HETE: 9-hydroxyeicosatetraenoic acid; Allantoin: 1-ureido-m-diazacyclopentane-2,4-dione; 15-HETE: 15-hydroxyeicosatetraenoic acid; Ceramide (d18:1 / 24:1): ceramide (d18:1 / 24:1).

[0065] Figure 8 shows that paeoniflorin significantly enhances the metabolism of intestinal flora in rats (Top 25 metabolites with significant changes after administration, VIP>1.5 indicates significant difference).

[0066] The figure shows the top 25 compounds with significant differences in gut microbiota metabolism among rats in the normal control group, CUMS group, and paeoniflorin (Alb) group, listed in descending order of significance: p-Aminohippuric acid; PE (36:3); Pyridoxal; Pyroglutamic acid; 9-HETE; Ceramide (d18:1); Glycocholic acid; Adenosine; Docosahexaenoic acid; Chenodeoxyglycocholic acid; Choline; L-Tyrosine; Citrulline; Methylcysteine; Choline; L-Tyrosine; Citrulline; Methylcysteine; Choline; L-Tyrosine; Citrulline; Methylcysteine; acetyl ... acid: cholic acid; 15-HETE: 15-hydroxyeicosatetraenoic acid; L-Lysine: L-lysine; Dimethylglycine: dimethylglycine; Glycine: glycine; Allantoin: 1-ureido-m-diazacyclopentane-2,4-dione; 14,15-Epoxy-5,8,11-eicosatrienoic acid: 14,15-epoxy-5,8,11-eicosatrienoic acid; L-Glutamic acid: L-glutamic acid; L-Threonine: L-threonine; Alanine: alanine; Propionic acid: propionic acid.

[0067] Figure 9 shows that fluoxetine has a significant inhibitory effect on the intestinal flora metabolism of CUMS rats (Top 25 metabolites with significant changes after administration, VIP>1.5 indicates significant difference).

[0068] The figure shows the top 25 compounds with significant differences in gut microbiota metabolism among the normal control group, CUMS group, and fluoxetine (FLX) group, listed in descending order of significance: Pyridoxal; L-Tryptophan; L-Threonine; L-Tyrosine; Homoarginine; D-Glyceraldehyde 3-phosphate; 9-HETE; 14,15-Epoxy-5,8,11-eicosatrienoic acid; Allantoic acid; Alanine; Sarcosine; L-Serine; Ornithine; Ureidosuccinic acid. acid: ureosuccinic acid; L-Methionine: L-methionine; L-Kynurenine: L-kynurenine; L-Lysine: L-lysine; Glycocholic acid: glycocholic acid; L-Phenylalanine: L-phenylalanine; Uridine: uridine; Deoxyadenosine: deoxyadenosine; Indole: indole; Methylcysteine: methyl acetylcysteine; Aspartylglycosamine: aspartic acid glucosamine; L-Proline: L-proline

[0069] Figure 10 is a bar chart of relative abundance of species at the family level. (Based on the species annotation results, the top 10 species with the highest abundance at the family level in each sample group were selected, and the relative abundance bars were accumulated to visually show the species with high relative abundance and their proportion in the sample group at the family level. The horizontal axis (Group Name) represents the group name, control is the blank control, CUMS is the depression model group, Alb is the paeoniflorin group; Pae is the paeoniflorin group, and BA is the benzoic acid group; the vertical axis (Relative Abundance) represents the relative abundance; Others represents the sum of the relative abundance of all other families besides the 10 families shown in the figure.)

[0070] Figure 11 shows the comparison of the ratio of Bacteroides to Firmicutes in feces (B / F ratio) between the paeoniflorin group and the CUMS group, where Sal is physiological saline and Alb is paeoniflorin. Detailed Implementation

[0071] The present invention will be further illustrated below with specific implementation examples. However, the following implementation examples are merely illustrative of the invention and are not intended to limit the scope of the invention.

[0072] Example 1: Effects of paeoniflorin on serotonin metabolism pathway and IDO and MT1 in CUMS rats

[0073] First, a slow stress rat model (CUMS) was established using methods known in the art. Targeted metabolomics was then used to investigate the effects of serotonin metabolism and IDO in CUMS rats. Through multivariate analysis (PLS-DA, OPLS-DA, and VIP analyses), it was found that paeoniflorin upregulates the serotonin metabolism pathway, downregulates the kynurenine metabolism pathway (Figure 1), inhibits IDO overactivation, and increases endogenous melatonin (MT1) secretion, thus exhibiting antidepressant effects, improving sleep, and preventing metabolic syndrome comorbid with depression (Mets).

[0074] The experimental results are shown in Table 1, Figures 2, 3, and 4.

[0075] Table 1. Effects of paeoniflorin on serotonin metabolism in rats

[0076] # indicates a significant increase compared to CUMS (P<0.05); ## indicates a significant increase compared to CUMS (P<0.01); ** indicates a significant decrease compared to CUMS (P<0.01).

[0077] From the experimental results in Table 1 and Figures 2, 3, and 4, we can see that:

[0078] 1. Compared with the blank control group (i.e., the normal group, Control group), the hippocampal serotonin metabolism pathway in the CUMS group model rats was inhibited and downregulated (↓), while the kynurenine metabolism pathway was upregulated (i.e., the concentration of metabolites of the kynurenine metabolism pathway was upregulated) (↑), resulting in a decrease in serotonin content (↓) and an increase in IDO activity (↑).

[0079] 2. After administration of paeoniflorin (Alb), the levels of kynurenine and quinolinic acid in the hippocampus of rats in the paeoniflorin group were significantly lower than those in the CUMS group (↓), while the serotonin level was significantly increased (↑). IDO was inhibited and significantly downregulated (↓) (P<0.01, see Table 1 and Figure 2). Melatonin and melatonin receptor 1A were significantly upregulated (↑), and their concentrations were significantly increased (P<0.01, Figure 3 and Figure 4).

[0080] 3. Fluoxetine (Flx) was administered. Its effect was opposite to that of paeoniflorin. In the fluoxetine group, IDO in the hippocampus of rats was significantly upregulated (↑) (P<0.05, Figure 2), and melatonin and melatonin receptor 1A were significantly downregulated (↓), with the concentration now reduced (P<0.01, Figures 3 and 4).

[0081] Example 2: Effects of paeoniflorin on gut microbiota metabolism in CUMS model rats

[0082] The inventors used a targeted metabolomics research method to simultaneously determine the concentration of 430 common metabolites with important physiological and biochemical functions in the gut microbiota, and used LC / MSn-IT-TOF method to identify the metabolites in the feces of ICR mice in each group; these 430 metabolites are distributed in 46 key gut microbiota metabolic pathways.

[0083] The experimental results are shown in Figures 5, 6, 7, 8, and 9.

[0084] The experimental results show that:

[0085] 1. As shown in Figure 5, PLA-DA multivariate analysis of the concentrations of 430 metabolites measured in the experiment revealed significant differences between the intestinal flora metabolite concentrations in the CUMS group (model group) and the normal group (blank control group, Control group, Ctrl). The two groups were almost completely separated in the two-dimensional plot, indicating that the intestinal flora metabolic balance in the CUMS group model rats was disrupted. However, after treatment with paeoniflorin (Alb), the intestinal flora metabolism of the rats tended to recover towards the direction of the normal control group, almost completely overlapping, indicating that paeoniflorin can significantly restore normal intestinal flora metabolism.

[0086] 2. As shown in Figure 6, when CUMS model rats were treated with fluoxetine (Flx), the results were the opposite. Fluoxetine caused the intestinal flora metabolism of CUMS rats to deviate further from that of the normal control group, which further damaged the intestinal flora metabolism of the depression model rats.

[0087] 3. VIP analysis showed that the gut microbiota metabolism of CUMS rats was significantly reduced compared with the normal group. Among the top 25 metabolites with significant differences in the gut microbiota of CUMS group and normal group rats, 16 metabolites (80%) in CUMS group rats were significantly reduced (VIP>1.5), as shown in Figure 7.

[0088] 4. VIP analysis showed that the overall metabolism of intestinal flora in the paeoniflorin-treated group was significantly improved compared with the CUMS group, mainly manifested in increased bile acid content, increased amino acid and vitamin content, indicating that paeoniflorin significantly upregulated the beneficial metabolism of intestinal flora, thereby improving and enhancing intestinal flora function, as shown in Figure 8.

[0089] 5. VIP analysis showed that administration of fluoxetine severely suppressed the overall metabolism of the gut microbiota in the fluoxetine group rats, as shown in Figure 9. The levels of all 25 (100%) most significantly different metabolites in the feces of the fluoxetine group rats were significantly reduced, and lower than those in the CUMS group, mainly manifested as a decrease in bile acid content, and a decrease in amino acid and vitamin content. This suggests that fluoxetine severely disrupts the metabolic balance of the gut microbiota in depressed rats, inducing and aggravating metabolic syndrome comorbid with depression (Mets).

[0090] The results showed that paeoniflorin can prevent and treat metabolic syndrome comorbid with depression (Mets) by improving the metabolic function of intestinal flora and increasing the production of bile acids, amino acids and vitamins; fluoxetine, on the other hand, further aggravated the metabolic dysfunction of intestinal flora, inhibited the secretion of metabolites such as bile acids, and increased the risk of developing metabolic syndrome comorbid with depression (Mets).

[0091] Example 3: Effects of paeoniflorin on gut microbiota ecology in CUMS model rats

[0092] 1. OTUs analysis and gut microbiota species identification

[0093] The intestinal flora of rats in the normal control group, CUMS model group, paeoniflorin group, and fluoxetine group were identified by 16S rDNA. The experimental results are shown in Table 2 and Figures 10 and 11.

[0094] Table 2. Relative abundance (%) of the top 10 most abundant species at the family level

[0095] As shown in Figure 10 and Table 2, the top 10 most abundant species at the family level are Prevostidae, Lactobacillusaceae, Bacteroidetes S24-7, and Trichophytonceae. The proportions of these dominant bacteria in the normal control group (blank group) and the CUMS group are different. Except for Prevostidae, which is significantly higher in feces in the CUMS group than in the normal control group, the other nine families are lower in feces in the CUMS group than in the normal control group to varying degrees.

[0096] The relative abundance of Prevostiaceae in the feces of the CUMS group was significantly higher than that of the normal group, indicating that slow stress caused disorders in energy metabolism, lipid metabolism, and glucose metabolism in rats. Paeoniflorin significantly reduced the relative abundance of Prevostiaceae in rat feces, which is consistent with the metabolomics and transcriptomics results that paeoniflorin can alleviate metabolic syndrome comorbid with depression (Mets) by affecting energy metabolism in rats.

[0097] 2. Determination of the ratio (B / F) of Bacteroides (B) to Firmicutes (F) in feces of the paeoniflorin group and CUMS group.

[0098] Bacteroides and Firmicutes are the main components of the rat gut microbiota, and changes in the Bacteroides / Firmwares ratio (B / F) are a key indicator of gut microbiota imbalance.

[0099] Compared with the normal control group (blank group), the abundance of Bacteroides and the B / F ratio in the feces of the CUMS group were increased (↑), as shown in Figure 11 (P<0.05), indicating that CUMS disrupted the balance of the intestinal flora in rats. After administration of paeoniflorin, the B / F ratio decreased significantly compared with the CUMS group (P<0.05) (↓), indicating that paeoniflorin alleviated the CUMS-induced intestinal flora imbalance in rats and reduced the risk of metabolic syndrome (Mets) induced by depression.

[0100] Therefore, paeoniflorin reduces the risk of metabolic syndrome (Mets) caused by depression by improving gut microbiota dysbiosis in patients with depression, reducing Prevotella abundance (↓), decreasing the ratio of Bacteroides to Firmicutes (B / F↓).

Claims

1. The use of paeoniflorin and white peony extract in the preparation of drugs, health foods, dietary supplements, and functional gummies for the prevention and / or treatment of metabolic syndrome comorbid with depression, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

2. The application as described in claim 1, characterized in that, The aforementioned metabolic syndrome comorbid with depression includes conditions such as obesity, hyperlipidemia, hypertension, hyperglycemia, energy metabolism disorders, and cardiovascular diseases.

3. A combination drug of paeoniflorin or white peony extract with monoamine antidepressants such as SSRIs, which enhances antidepressant efficacy and reduces the risk of drug-induced metabolic syndrome (Mets) induced by monoamine antidepressants such as SSRIs, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

4. Use of a paeoniflorin glycoside and a white peony extract in the prevention and / or treatment of type 2 diabetes; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression induced by enterobiotic DPP-4; preferably in the prevention and / or treatment of type 2 diabetes comorbid with depression induced by IDO1 overactivation, wherein the white peony extract is a paeoniflorin glycoside containing a therapeutic amount.

5. A combination drug of paeoniflorin or white peony extract with human-derived DPP-4 inhibitors such as sitagliptin, enhancing the efficacy against type 2 diabetes mellitus comorbid with depression induced by enteropathogenic DPP-4 or IDO1 overactivation, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

6. A combination drug of paeoniflorin or white peony extract and statins, used to enhance efficacy and reduce side effects, synergistically prevent and treat cardiovascular diseases comorbid with depression, and reduce the risk of type 2 diabetes induced by statins, wherein the white peony extract contains a therapeutic amount of paeoniflorin.

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