Use of 3-indolebutyric acid in the preparation of a medicament for the treatment of chronic heart failure

Abstract

This invention discloses the application of 3-indolebutyric acid (3-IBA) in the preparation of drugs for treating chronic heart failure, belonging to the field of disease detection and biomedical technology. This invention is the first to discover that the plasma 3-IBA level in heart failure patients is significantly decreased, which can serve as an auxiliary diagnostic and risk assessment biomarker for chronic heart failure. 3-IBA metabolites can specifically bind to and activate AhR targets, precisely regulating related signaling pathways in myocardial tissue, avoiding non-specific effects on other tissues and organs, and reducing side effects. By activating AhR, it upregulates SIRT3, inhibits NNMT, and enhances NAM and NAD+ / NADH cycles, fundamentally improving myocardial mitochondrial energy metabolism, while simultaneously reducing oxidative stress, inhibiting chronic inflammatory responses, and reversing ventricular remodeling, thus achieving etiological treatment of heart failure.

Description

Technical Field

[0001] This invention belongs to the field of disease detection and biomedicine technology, specifically relating to the application of 3-indolebutyric acid in the preparation of drugs for treating chronic heart failure. Background Technology

[0002] Chronic heart failure (CHF) is the end-stage of many cardiovascular diseases and one of the leading causes of hospitalization and death among cardiovascular disease patients worldwide. Its core pathogenesis involves excessive activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, and a relative deficiency of the natriuretic peptide system, triggered by myocardial injury. This leads to ventricular remodeling (myocardial hypertrophy, cardiomyocyte apoptosis, interstitial fibrosis), myocardial energy metabolism disorders, excessive activation of oxidative stress, and persistent chronic inflammation, ultimately resulting in a progressive decline in cardiac systolic / diastolic function.

[0003] Currently, commonly used drugs for treating heart failure mainly include angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, and aldosterone receptor antagonists. While these drugs can improve heart failure symptoms and slow disease progression to some extent, they still suffer from insufficient targeting, poor efficacy in some patients, and side effects such as liver and kidney damage with long-term use. Furthermore, there is no specific treatment for heart failure with preserved ejection fraction (HFpEF); existing treatments only address the symptoms and cannot fundamentally improve myocardial diastolic function and energy metabolism disorders.

[0004] Aromatic hydrocarbon receptors (AhRs) are important nuclear receptors whose expression and activation status in myocardial tissue are closely related to the development and progression of heart failure. Studies have found that activating AhR can upregulate SIRT3 expression and inhibit NNMT activity, thereby improving myocardial mitochondrial energy metabolism and reducing oxidative stress and inflammatory responses. 3-Indolebutyric acid (3-IBA), as an endogenous metabolite, has good biocompatibility and safety, but its role in targeting AhR for the treatment of heart failure has not yet been disclosed.

[0005] Therefore, developing 3-IBA-based diagnostic and treatment strategies for heart failure has significant clinical value. Summary of the Invention

[0006] The purpose of this invention is to provide an application of 3-indolebutyric acid in the preparation of drugs for treating chronic heart failure, which can solve the problems of insufficient diagnostic markers for heart failure, poor targeting of therapeutic drugs, and obvious side effects in the prior art.

[0007] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution: The use of 3-indolebutyric acid in the preparation of drugs for the treatment of chronic heart failure.

[0008] In one or more embodiments of the present invention, the drug exerts a therapeutic effect by activating the aryl hydrocarbon receptor signaling pathway.

[0009] In one or more embodiments of the present invention, the chronic heart failure includes heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.

[0010] In one or more embodiments of the present invention, the drug uses 3-indolebutyric acid as the sole active ingredient, or uses 3-indolebutyric acid in combination with other heart failure treatment drugs as active ingredients; the other heart failure treatment drugs are selected from at least one of angiotensin receptor neprilysin inhibitors, β-blockers, and aldosterone receptor antagonists.

[0011] In one or more embodiments of the present invention, the dosage form of the drug is an oral preparation or an injectable preparation; the oral preparation is a tablet, capsule or granule, and the injectable preparation is an injection solution or a lyophilized powder for injection.

[0012] In one or more embodiments of the present invention, the treatment of chronic heart failure is achieved by at least one of the following methods: reducing myocardial fibrosis, improving cardiac function, and reducing BNP marker levels.

[0013] Application of reagents for detecting 3-indolebutyric acid levels in the preparation of kits for diagnosing or assessing the risk of chronic heart failure.

[0014] In one or more embodiments of the present invention, the reagent for detecting 3-indolebutyric acid levels is used in the preparation of a kit for diagnosing or assessing the risk of chronic heart failure.

[0015] In one or more embodiments of the present invention, the kit diagnoses or assesses the risk of chronic heart failure by detecting the concentration of 3-indolebutyric acid in a biological sample; when the concentration of 3-indolebutyric acid is significantly lower than a preset normal reference value, it indicates that the subject has a risk of chronic heart failure or is already in a pathological state.

[0016] In one or more embodiments of the present invention, the kit further comprises a reagent for detecting the abundance of gut microbiota, wherein the gut microbiota is Bacteroides uniformis.

[0017] A pharmaceutical composition for treating chronic heart failure, the pharmaceutical composition comprising a therapeutically effective amount of 3-indolebutyric acid and pharmaceutically acceptable excipients.

[0018] Compared with existing technologies, this invention is the first to discover that the level of 3-IBA in the plasma of patients with heart failure is significantly reduced, which can be used as an auxiliary diagnostic and risk assessment biomarker for chronic heart failure.

[0019] 3-IBA metabolites can specifically bind to and activate AhR targets, precisely regulate related signaling pathways in myocardial tissue, avoid non-specific effects on other tissues and organs, and reduce side effects. By activating AhR to upregulate SIRT3, inhibit NNMT, and enhance NAM and NAD+ / NADH cycles, they fundamentally improve myocardial mitochondrial energy metabolism, while reducing oxidative stress, inhibiting chronic inflammatory responses, and reversing ventricular remodeling, thus achieving etiological treatment of heart failure.

[0020] It can be used to treat heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), and in particular, it solves the clinical problem of having no specific treatment for HFpEF.

[0021] 3-IBA is an endogenous metabolite with good biocompatibility, no obvious toxic side effects, and is suitable for long-term use.

[0022] It can be prepared into various dosage forms such as oral and injectable to meet the drug administration needs of different clinical scenarios, and can achieve synergistic effects when used in combination with existing heart failure drugs to improve clinical efficacy. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 A shows echocardiographic images of non-heart failure (Non-HF) and heart failure (HF) donors in parasternal long-axis and short-axis views. B shows a comparison of ejection fraction and fractional shortening data between the Non-HF and HF groups. C shows the upper part of the mitral valve flow Doppler spectrum and the lower part of the corresponding HE-stained histological images. D shows a comparison of E / A ratio, peak E-wave velocity, and A-wave velocity data between the Non-HF and HF groups. E shows a comparison of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) concentration data between the Non-HF and HF groups. Figure 2In the diagram, A is the Venn diagram of the pig metagenomics and the human metagenomics; B is the principal coordinate analysis diagram of the human metagenomics; C is the box plot of the differences between the dHF and dHC groups; D is the principal coordinate analysis diagram of the pig metagenomics; and E is the linear discriminant analysis effect size analysis diagram of the Non-HF and HF groups. Figure 3 The left side shows the relative abundance of three different bacteria, B. ovatus-01, B. xylanisolvens-01, and B. uniformis-01, in the control group and the heart failure group (HF), while the right side shows a heatmap of the correlation between specific species and clinical indicators. Figure 4 The top section shows the principal coordinate analysis plot and volcano plot of XSVSCK; the middle section shows the correlation heatmap between specific metabolites in the blood and species; and the bottom section shows the comparison of expression levels of CYP1A1 and CYP1B1 in the control group and the heart failure group (HF). Figure 5 The top center shows UMAP maps of cell types, groups, and samples. The middle section shows heatmaps of specific gene expression in different cell types, three-dimensional scatter plots of cells, and stacked bar charts of cell types in different samples. The bottom left section shows gene expression heatmaps. The bottom middle section shows immunofluorescence staining images of the non-heart failure group (Non-HF) and the heart failure group (HF). The bottom right section shows a comparison of the expression levels of Collagen-1, Bcl2, BAX, and GAPDH proteins in the non-heart failure group (Non-HF) and the heart failure group (HF). Figure 6 The top left section shows the UMAP map of macrophages, the proportional distribution of macrophage subsets in the Non-HF and HF groups, the top middle section shows the bubble diagram of different pathways, and the differences between the Non-HF and HF groups in WBC (white blood cell count), LYM% (lymphocyte percentage), MON% (monocyte percentage), and NEU% (neutrophil percentage). The top right section shows the UMAP map of cardiomyocytes, the proportional distribution of cardiomyocyte subsets in the Non-HF and HF groups, the bottom left section shows the expression of CD3, CD68, and CD163 in the myocardial tissue of the Non-HF and HF groups, the bottom middle section shows the ultrastructure of cardiomyocytes in the Non-HF and HF groups, and the bottom right section shows the composition and function of the electron transport chain (ETC) in mitochondria. Figure 7The upper left of the middle section shows the appearance of the mouse heart in the Sham, Model, and 3-IBA groups; the middle left section shows the echocardiograms of the Sham, Model, and 3-IBA groups in the short-axis and long-axis views; and the right and lower left sections show the quantitative analysis results of multiple cardiac function and morphological indicators in the Sham, Model, and 3-IBA groups. Figure 8 The left-middle section shows a comparison of the expression levels of AHR, CYP1B1, and CYP1A1 proteins in the Sham, Model, and 3-IBA groups, while the right section shows a schematic diagram of the mechanisms of cardiac hypertrophy and dysfunction, as well as the protective effects of 3-IBA and B. uniformis. Figure 9 Image showing the results of AB-PAS staining of intestinal tissue sections from the Sham, Model, and 3-IBA groups; Figure 10 The relative abundance plots of Bacteriodes_uniformis-03, Bacteriodes_uniformis-02, Bacteriodes_uniformis-01, and Bacteriodes_uniformis-si in the Sham, Model, and 3-IBA groups are shown. Detailed Implementation

[0025] To enable those skilled in the art to better understand the technical solutions in this disclosure, the technical solutions in the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. Based on the embodiments in this disclosure, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this disclosure.

[0026] Example 1: Detection of 3-IBA levels in patients with heart failure and animal models Clinical sample collection: Fasting peripheral venous blood was collected from 50 patients diagnosed with chronic heart failure (HF) (HF group) and 50 age- and sex-matched healthy volunteers (control group). Plasma was separated by centrifugation and stored at -80℃ for later use. Inclusion criteria for the HF group: meeting the diagnostic criteria of the "Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018" and having a left ventricular ejection fraction (LVEF) <50%. Exclusion criteria: acute myocardial infarction, severe liver or kidney dysfunction, and malignant tumors.

[0027] Targeted metabolomics detection of 3-IBA concentration: The concentration of 3-IBA in plasma was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS). Chromatographic conditions: ACQUITY UPLC-BEHC18 column (2.1 × 100 mm, 1.7 μm); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; gradient elution. Mass spectrometry conditions: electrospray ionization negative ion mode, multiple reaction monitoring.

[0028] result:

[0029] The results showed that the plasma 3-IBA concentration in the heart failure group (8.7±3.1 ng / mL) was significantly lower than that in the healthy control group (28.4±6.2 ng / mL). Furthermore, 3-IBA concentration was positively correlated with LVEF and negatively correlated with BNP. These results indicate that 3-IBA can serve as an auxiliary diagnostic biomarker for chronic heart failure.

[0030] Example 2: Therapeutic effect of 3-IBA on aortic coarctation (TAC)-induced heart failure model mice Eight-week-old male C57BL / 6J mice, weighing 20-25g, were randomly divided into three groups of 10 mice each: Sham surgery group: The patient underwent open-chest surgery but without aortic coarctation. Postoperatively, the patient was given an equal volume of normal saline by gavage daily.

[0031] Model group: A chronic heart failure model was established by aortic coarctation (TAC), and the same volume of normal saline was administered by gavage daily after the operation.

[0032] 3-IBA treatment group (3-IBA): After TAC, 3-IBA (20 mg / kg, dissolved in normal saline) was administered by gavage daily for 4 consecutive weeks.

[0033] Cardiac function testing: Four weeks after drug administration, cardiac function in mice was assessed using the Vevo2100 ultrasound imaging system. Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVIDd), and left ventricular end-systolic diameter (LVIDs) were measured.

[0034] Myocardial fibrosis and BNP detection: Mice were sacrificed after ultrasound examination, and heart tissue was collected for Masson staining. Myocardial collagen volume fraction (CVF) was calculated. Plasma BNP levels were detected using an ELISA kit.

[0035] result: Table 1. Comparison of cardiac function and fibrosis indices in mice of different groups (Mean±SD, n=10)

[0036] The results showed that, compared with the Model group, the LVEF (59.3±4.8% vs 41.2±5.6%) and LVFS were significantly increased in the 3-IBA treatment group, while the LVIDd and LVIDs were significantly decreased. The myocardial collagen volume fraction (7.8±1.9% vs 18.5±3.2%) and plasma BNP level (215.6±45.2 vs 685.4±98.3 pg / mL) were also significantly reduced. These results indicate that 3-IBA can significantly improve cardiac function and alleviate myocardial fibrosis in TAC-induced heart failure mice.

[0037] Example 3: Mechanism verification of 3-IBA activation of the AhR signaling pathway Western Blot analysis: Proteins were extracted from the myocardial tissue of mice in each group, and the levels of AhR, CYP1A1, and CYP1B1 (downstream target genes of AhR) were detected by Western Blot.

[0038] result:

[0039] The results showed that, compared with the Model group, 3-IBA treatment significantly restored the protein expression levels of AhR, CYP1A1 and CYP1B1 in myocardial tissue, indicating that 3-IBA exerts a cardioprotective effect by activating the AhR signaling pathway.

[0040] Example 4: Combined use of 3-IBA with other heart failure drugs Combination dosing regimen: Another 30 TAC model mice were randomly divided into 3 groups of 10 mice each: 3-IBA monotherapy group: 3-IBA 20 mg / kg / day, by gavage.

[0041] Valsartan group: Valsartan 30 mg / kg / day, by gavage.

[0042] Combined group: 3-IBA (20 mg / kg / day) + valsartan (30 mg / kg / day), by gavage.

[0043] LVEF was measured after 4 weeks of continuous administration.

[0044] result:

[0045] The results showed that the combination of 3-IBA and valsartan produced a significant synergistic effect, increasing LVEF to 71.3±4.8%, which was significantly better than either monotherapy.

[0046] Example 5: Pharmaceutical Composition (Oral Tablets) Each tablet contains: 3-Indolebutyric acid: 50mg Microcrystalline cellulose: 80mg Lactose: 60mg Sodium carboxymethyl starch: 10mg Magnesium stearate: 2mg Preparation method: 3-IBA and excipients are passed through an 80-mesh sieve and mixed evenly using an equal-incremental method. The mixture is then compressed into tablets using the direct powder compression method to obtain the final product.

[0047] Example 6: Diagnostic Kit A kit for diagnosing chronic heart failure, comprising: 3-IBA Standard (Concentration gradient: 0.1, 0.5, 2, 10, 50, 200 ng / mL) 3-IBA-d5 internal standard Extract (methanol:acetonitrile = 1:1, containing 0.1% formic acid) Detection buffer The instruction manual states that the normal reference values ​​are: plasma 3-IBA concentration ≥15 ng / mL indicates low risk, <10 ng / mL indicates high risk. Instructions for use: Take 50 μL of the plasma to be tested, add internal standard and extraction solution, vortex centrifuge, and take the supernatant for UPLC-MS / MS analysis. Calculate the 3-IBA concentration in the sample and compare it with the normal reference value to assess the risk of heart failure.

[0048] Example 7: Clinical characteristics and differences in cardiac function between patients with heart failure and healthy controls (e.g., Figure 1 ) To clarify the clinical characteristics of heart failure donors used in this study, cardiac tissue and peripheral blood samples were collected from both non-heart failure (Non-HF) and heart failure (HF) donors according to the inclusion criteria in Example 1. Figure 1 As shown in Figure A, echocardiography revealed that the left ventricle was significantly enlarged and the ventricular wall motion was weakened in the HF group. Figure 1 The quantitative results of the study showed that the ejection fraction and fractional shortening in the HF group were significantly lower than those in the Non-HF group. Figure 1 The Doppler spectrum of mitral valve blood flow in the middle C group showed an increased E peak and a decreased A peak. Figure 1 Quantitative analysis of the E / A ratio, peak E-wave velocity, and A-wave velocity in the HF group further confirmed diastolic dysfunction. Meanwhile, Figure 1 The results showed that serum creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) levels were significantly elevated in the HF group, indicating myocardial injury. These results provide a clinical basis for the diagnostic biomarkers and therapeutic targets provided by this invention.

[0049] Example 8: Metagenomic analysis of gut microbiota associated with heart failure (e.g.) Figure 2 , Figure 3 ) To explore changes in gut microbiota during heart failure, metagenomic sequencing was performed on pig models and clinical samples. Figure 2 The Venn diagram in section A shows that there are a large number of overlapping microbial genes between the pig metagenomics and the human metagenomics. Figure 2 Principal coordinate analysis (PCoA) in the middle B showed a significant separation of gut microbiota structure between heart failure patients (dHF) and healthy controls (dHC); Figure 2 The box plot of the difference in C further confirmed this difference. Similarly, Figure 2 PCoA analysis of the pig metagenomics of the D-type pig model also showed that the microbial community structure was separated from that of the heart failure group and the control group. Figure 2 The linear discriminant analysis of the effect size (LEfSe) plot in the middle E was used to screen out the key bacterial genera enriched in the heart.

[0050] Further quantification of specific bacterial species, such as Figure 3 As shown on the left, compared with the Control group, the relative abundance of B. ovatus-01, B. xylanisolvens-01, and B. uniformis-01 in the HF group was significantly reduced. Figure 3 The correlation heatmap on the right shows that the abundance of these bacterial species is positively correlated with LVEF and negatively correlated with BNP and CK-MB. These results indicate that gut microbiota dysbiosis, particularly a reduction in species such as *Bacteroides uniformis*, is closely related to heart failure.

[0051] Example 9: Changes in heart failure-related metabolites and the AhR pathway (corresponding) Figure 4 ) Untargeted and targeted metabolomics analyses were performed on the above samples. Figure 4 The principal coordinate analysis (PCoA) and volcano plots showed significant differences in plasma metabolic profiles between the heart failure group and the control group, with alterations in multiple indole metabolites. Figure 4 The correlation heatmap in the central region showed that metabolites such as 3-indolebutyric acid (3-IBA) in the blood were significantly positively correlated with the abundance of bacterial species such as B. uniformis. Figure 4 The bottom panel shows that, compared to the Control group, the expression levels of AhR downstream target genes CYP1A1 and CYP1B1 in myocardial tissue were significantly reduced in the HF group. This result suggests that in heart failure, a decrease in 3-IBA derived from gut microbiota leads to suppression of the AhR signaling pathway.

[0052] Example 10: Single-cell transcriptomics reveals changes in the myocardial microenvironment in heart failure (e.g., Figure 5 , Figure 6 ) To elucidate the mechanisms of heart failure at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed on cardiac tissues from both non-HF and HF donors. Figure 5 The top UMAP diagram shows the distribution of different cell types (cardiomyocytes, fibroblasts, endothelial cells, macrophages, etc.), groups, and samples. Figure 5 The heatmap and 3D scatter plot in the middle show significant changes in the expression profile of specific genes in the heart failure group, and the stacked bar plot shows an increase in the proportion of fibroblasts and macrophages in the heart failure group. Figure 5 The gene expression heatmap in the lower left shows that fibrosis-related genes (Col1a1, Col3a1) are upregulated in the HF group; Figure 5 Immunofluorescence staining of the middle and lower parts showed increased Collagen-1 deposition in the myocardial tissue of the HF group; Figure 5 The Western Blot results in the lower right corner show that the anti-apoptotic protein Bcl2 is decreased and the pro-apoptotic protein BAX is increased in the HF group.

[0053] Further analysis of macrophage and cardiomyocyte subsets was conducted. Figure 6 The upper left shows that macrophages can be subdivided into multiple subsets, and the proportion of pro-inflammatory subsets is increased in the heart failure group (the bubble chart in the upper middle part shows the activation of inflammation-related pathways). At the same time, peripheral blood WBC and NEU% are increased, while LYM% is decreased. Figure 6 (Above average). Figure 6 The upper right corner shows the analysis of cardiomyocyte subsets, which shows an increased proportion of stress-induced cardiomyocyte subsets in the heart failure group. Figure 6 The lower left image shows immunohistochemistry confirming increased infiltration of CD3+ T cells, CD68+ and CD163+ macrophages in heart failure myocardial tissue. Figure 6 Mid-to-lower range transmission electron microscopy revealed mitochondrial swelling and cristae breakage in cardiomyocytes of the heart failure group; Figure 6 The lower right corner shows reduced activity of the electron transport chain complex. These data reveal the cellular and molecular mechanisms of heart failure from multiple dimensions, providing a theoretical basis for 3-IBA treatment of heart failure.

[0054] Example 11: The protective effect of 3-IBA on gut microbiota and intestinal barrier in mice with heart failure (e.g.) Figure 9 , Figure 10 ) Based on Example 2, intestinal tissue and contents of mice in each group were collected. Figure 9 AB-PAS staining results showed that, compared with the Sham group, the Model group had a thinner intestinal mucus layer and fewer goblet cells, while the 3-IBA treatment group showed significant improvement in the above indicators, indicating that 3-IBA can protect the intestinal barrier function. Figure 1016S rRNA sequencing results showed that the relative abundance of *Bacteroides_uniformis* and its operational taxonomic units (OTUs, such as *Bacteriodes_uniformis-03, -02, -01, -si*) in the Model group was significantly lower than that in the Sham group, while the abundance of this bacterium was partially restored in the 3-IBA treatment group. Figure 4 The results suggest that 3-IBA may exert cardioprotective effects through the gut microbiota-metabolite-AhR axis.

[0055] Example 12: Schematic diagram of the comprehensive mechanism of 3-IBA in treating heart failure (e.g.) Figure 8 ) In summary, the above embodiments, Figure 8 The Western Blot results on the left (consistent with those in Example 3) showed that 3-IBA restored the expression of AhR, CYP1B1, and CYP1A1 in the myocardium of mice with heart failure. Figure 8 The right side summarizes the mechanism proposed in this invention: In the state of heart failure, the reduction of gut microbiota (especially B. uniformis) leads to a decrease in the level of its metabolite 3-IBA, which in turn leads to the suppression of the myocardial AhR signaling pathway, causing mitochondrial dysfunction, oxidative stress, inflammation and fibrosis; supplementing with exogenous 3-IBA can reactivate the AhR pathway, improve cardiac function and reduce ventricular remodeling.

[0056] Example 13: Optimization of Diagnostic Kit Based on Example 6, the diagnostic kit was further optimized to simultaneously detect 3-IBA levels and Bacteroides uniformis abundance. Specifically, the kit further comprises: Specific primer pairs (forward: 5'-GGTTAGCTCCGTTACGGAC-3'; reverse: 5'-CCCATGGTGTGACGGGCGG-3') and fluorescent probes targeting the Bacteroides uniformis 16S rRNA gene; Fecal DNA extraction reagent; qPCR reaction solution.

[0057] Method of use: The plasma 3-IBA concentration (same method as in Example 6) and the Ct value of B. uniformis in feces were measured separately in the subjects. When "plasma 3-IBA <10 ng / mL" and "the relative abundance of B. uniformis in feces is reduced by more than 50% compared with the normal reference value", the subject was judged to be at high risk of chronic heart failure. The sensitivity and specificity of this combined diagnostic method are higher than those of a single biomarker.

[0058] This invention can effectively diagnose or assess the risk of chronic heart failure by detecting 3-IBA levels; by administering 3-IBA monotherapy or in combination with other heart failure drugs, cardiac function can be significantly improved and myocardial fibrosis can be reduced, the mechanism of which is related to the activation of the AhR signaling pathway.

[0059] It will be apparent to those skilled in the art that this disclosure is not limited to the details of the exemplary embodiments described above, and that this disclosure can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of this disclosure is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within this disclosure. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0060] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

The use of 1,3-indolebutyric acid in the preparation of drugs for the treatment of chronic heart failure.

2. The application according to claim 1, characterized in that, The drug exerts its therapeutic effect by activating the aryl hydrocarbon receptor signaling pathway.

3. The application according to claim 1 or 2, characterized in that, The chronic heart failure includes heart failure with reduced ejection fraction or heart failure with preserved ejection fraction.

4. The application according to claim 1, characterized in that, The drug uses 3-indolebutyric acid as the sole active ingredient, or uses 3-indolebutyric acid in combination with other heart failure treatment drugs as active ingredients; the other heart failure treatment drugs are selected from at least one of angiotensin receptor neprilysin inhibitors, β-blockers, and aldosterone receptor antagonists.

5. The application according to claim 1, characterized in that, The dosage form of the drug is an oral preparation or an injectable preparation; the oral preparation is a tablet, capsule or granule, and the injectable preparation is an injection solution or lyophilized powder for injection.

6. The application according to claim 1, characterized in that, The treatment of chronic heart failure is achieved through at least one of the following methods: reducing myocardial fibrosis, improving cardiac function, and lowering BNP marker levels.

7. Application of reagents for detecting 3-indolebutyric acid levels in the preparation of kits for diagnosing or assessing the risk of chronic heart failure.

8. The application according to claim 7, characterized in that, The kit diagnoses or assesses the risk of chronic heart failure by detecting the concentration of 3-indolebutyric acid in biological samples; when the concentration of 3-indolebutyric acid is significantly lower than the preset normal reference value, it indicates that the subject is at risk of chronic heart failure or is already in a pathological state.

9. The application according to claim 7, characterized in that, The kit also includes reagents for detecting the abundance of gut microbiota, which is Bacteroides uniformis.

10. A pharmaceutical composition for treating chronic heart failure, characterized in that, The pharmaceutical composition comprises a therapeutically effective amount of 3-indolebutyric acid and pharmaceutically acceptable excipients.

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