Application of Bacteroides uniformis as a diagnostic marker and therapeutic target for chronic heart failure
By using Bacteroides uniformis as a diagnostic marker and therapeutic target, the problem of insufficient targeting of existing heart failure treatments has been solved, enabling precise intervention and safe treatment of chronic heart failure, improving cardiac function and repairing the intestinal barrier.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- INST OF LAB ANIMAL SCI CHINESE ACAD OF MEDICAL SCI
- Filing Date
- 2026-05-30
- Publication Date
- 2026-07-31
AI Technical Summary
Existing heart failure treatments suffer from insufficient targeting, limited efficacy, poor response in some patients, and potential side effects such as liver and kidney damage with long-term use. Furthermore, there is a lack of targeted intervention strategies against single key bacterial species.
Bacteroides uniformis was used as a diagnostic biomarker and therapeutic target for chronic heart failure. Early risk assessment and disease grading were performed by detecting the abundance of B. uniformis in fecal samples. A probiotic preparation with B. uniformis as the active ingredient was prepared to promote the production of 3-indolebutyric acid (3-IBA), activate the AhR-CYP1A1 signaling pathway, and improve myocardial fibrosis and cardiac function.
It enables precise, efficient, and safe intervention for chronic heart failure, improves cardiac contractile function, reduces myocardial fibrosis, repairs the intestinal mucus layer, and provides an integrated diagnosis and treatment management model.
Smart Images
Figure CN122478968A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of microbial medicine and disease detection technology, specifically involving the application of Bacteroides homogeneus as a diagnostic biomarker and therapeutic target for 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 patients worldwide. Hypertension is prevalent in up to 57.2% of heart failure patients, and hypertension, through persistent stress overload, is one of the most important risk factors driving the development of heart failure with reduced ejection fraction (HFrEF). Its core pathogenesis involves ventricular remodeling (myocardial hypertrophy, cardiomyocyte apoptosis, interstitial fibrosis), myocardial energy metabolism disorders, excessive activation of oxidative stress, and persistent chronic inflammation, ultimately leading to 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 have problems such as insufficient targeting, poor efficacy in some patients, and side effects such as liver and kidney damage with long-term use. For heart failure with preserved ejection fraction (HFpEF), there are currently no specific drugs for treatment, and there is an urgent need to develop new intervention methods.
[0004] In recent years, a growing body of research has demonstrated that gut microbiota dysbiosis plays a crucial role in the development and progression of heart failure through the gut-heart axis. Dysbiosis leads to impaired intestinal barrier function, translocation of bacteria and their products (such as LPS), and triggers systemic inflammatory responses. Simultaneously, reduced production of protective short-chain fatty acids (SCFAs) and accumulation of harmful metabolites (such as TMAO) collectively drive myocardial fibrosis and cardiac dysfunction, creating a vicious cycle. However, no studies have yet clearly identified the specific bacterial species most closely associated with core clinical indicators of heart failure, nor have any targeted intervention strategies for single key bacterial species been developed and published, leaving this gap to be filled.
[0005] Therefore, in response to the above-mentioned technical problems, it is necessary to provide the application of Bacteroides homogeneous as a diagnostic biomarker and therapeutic target for chronic heart failure. Summary of the Invention
[0006] The purpose of this invention is to provide the application of Bacteroides homogeneous as a diagnostic biomarker and therapeutic target for chronic heart failure, which can solve the technical problems mentioned in the background art.
[0007] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution: The purpose of this invention is to provide the application of Bacteroides uniformis (B. uniformis) in the diagnosis and treatment of chronic heart failure. Addressing the shortcomings of existing heart failure treatments, such as insufficient targeting, limited efficacy, poor response in some patients, and potential side effects like liver and kidney damage with long-term use, this invention proposes a diagnostic and treatment regimen for chronic heart failure based on the key intestinal commensal bacterium B. uniformis. This aims to achieve precise, efficient, and safe intervention for chronic heart failure, especially hypertension-associated heart failure with reduced ejection fraction (HFrEF).
[0008] This invention also provides the application of *B. uniformis* abundance as a metabolic biomarker in the preparation of diagnostic kits for chronic heart failure. By detecting the relative abundance of *B. uniformis* in fecal or intestinal contents samples, it can be used for early risk assessment, disease grading, and treatment monitoring of chronic heart failure. A significantly lower *B. uniformis* abundance than the healthy reference value indicates a risk of heart failure, and its abundance changes are significantly correlated with clinical indicators such as EF%, LVIDd, LVPW, IVS, and NYHA functional classification, which can help assess the degree of cardiac function impairment.
[0009] To achieve the above objectives, this invention provides the application of *B. uniformis* in the preparation of targeted therapeutic drugs and diagnostic kits for heart failure, as well as a probiotic preparation for heart failure treatment using *B. uniformis* as the active ingredient. The therapeutic drug can be prepared in pharmaceutically acceptable dosage forms such as probiotic preparations, oral capsules, granules, lyophilized powder, or enteric-coated tablets. The *B. uniformis* is preferably an active strain capable of stably colonizing the intestine and promoting 3-IBA production. The diagnostic kit may include detection reagents and / or test strips, primers, probes, standards, quality control materials, and a data analysis module for detecting the abundance of *B. uniformis*.
[0010] Through fecal metagenomic analysis of heart failure patients and healthy controls, this invention found that *B. uniformis* abundance was significantly decreased in heart failure patients, and this was also validated in a human heart failure microbiota transplantation germ-free pig model. Further species-clinical marker correlation analysis showed that *B. uniformis* was significantly negatively correlated with multiple core clinical markers, including ejection fraction (EF%), left ventricular posterior wall thickness (LVPW), left ventricular end-diastolic diameter (LVIDd), interventricular septal thickness (IVS), and NYHA functional classification. It was the key species with the most associated markers and the strongest correlations among all differentially expressed bacterial species.
[0011] It is important to clarify that *B. uniformis* is significant not merely because it is a differentially expressed species in the gut microbiota of heart failure patients, but because it simultaneously meets several criteria: "significantly altered in disease states," "validated in human microbiota transplantation animal models," "significantly correlated with multiple core clinical indicators," "able to improve heart failure phenotypes through intervention experiments," and "possessing clearly defined metabolite and signaling pathway mechanisms." Therefore, *B. uniformis* in this invention has the dual value of being both a diagnostic biomarker and a therapeutic target.
[0012] Mechanistic studies have shown that *B. uniformis* can promote intestinal tryptophan metabolism to synthesize 3-indolebutyric acid (3-IBA)—a potent endogenous ligand for the aryl hydrocarbon receptor (AhR). In heart failure, *B. uniformis* depletion leads to reduced 3-IBA production and insufficient activation of AhR and its downstream target gene CYP1A1, thereby accelerating myocardial fibrosis. Reinfusion of *B. uniformis* can restore 3-IBA levels and activate the AhR-CYP1A1 signaling pathway, thereby alleviating myocardial fibrosis and improving cardiac contractile function.
[0013] In a mouse model of heart failure with aortic arch stenosis (TAC), intervention with *B. uniformis* significantly improved cardiac ejection fraction (EF%) and fractional shortening (FS%), and significantly reduced the heart weight / tibia length ratio (HW / TL) and lung weight / tibia length ratio (LW / TL), alleviated myocardial fibrosis, and repaired the intestinal mucus layer. When combined with an AhR inhibitor (AHRI), these protective effects were completely reversed, demonstrating that the cardioprotective effect of *B. uniformis* depends on the AhR signaling pathway.
[0014] The mechanism of action can be understood as follows: In chronic heart failure, the gut microbiota structure is disrupted, and the abundance of *B. uniformis* decreases significantly, leading to a reduction in the level of 3-IBA mediated or promoted by *B. uniformis*. This results in insufficient activation of the AhR-CYP1A1 protective signaling pathway, further aggravating myocardial fibrosis and cardiac function damage. Supplementing or reinfusing *B. uniformis* can restore the balance of the gut microbiota, promote 3-IBA production, and activate AhR and its downstream target gene CYP1A1, thereby alleviating myocardial fibrosis, improving cardiac contractile function, and repairing the intestinal mucus layer and intestinal barrier function. This mode of action differs from traditional drug treatments that solely target the heart itself; instead, it protects the heart by regulating the gut microbiota and gut-derived metabolites.
[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: B. uniformis is a specific bacterial species that is significantly associated with core clinical indicators of heart failure such as EF%, LVIDd, LVPW, IVS, and NYHA functional classification. It is the key bacterial species with the most associated indicators and the strongest correlation among all differential bacterial species, and therefore it is more targeted than ordinary broad-spectrum probiotic intervention. This invention clarifies that B. uniformis exerts its effects through the 3-IBA / AhR / CYP1A1 signaling axis, and verifies the necessity of this mechanism through AhR inhibitor reversal experiments; In the TAC heart failure mouse model, B. uniformis intervention can improve EF% and FS%, reduce HW / TL and LW / TL, alleviate myocardial fibrosis, and repair the intestinal mucus layer; B. uniformis is a commensal bacterium in the human gut and theoretically has good biocompatibility. At the same time, no obvious toxic damage was observed in the hepatic acid staining of important organs such as liver, lungs and kidneys in animal experiments, making it suitable for long-term chronic disease management. B. uniformis abundance can serve as an auxiliary diagnostic and risk assessment indicator for chronic heart failure, and also as a therapeutic intervention target, improving cardiac function through B. uniformis reinfusion or supplementation. The B. uniformis drug can also be used in combination with existing heart failure treatments, including ARNI, β-blockers, aldosterone receptor antagonists, etc., to achieve synergistic effects. From a clinical translation perspective, this invention provides a relatively complete technical pathway. It can determine the risk and severity of chronic heart failure by detecting the abundance of B. uniformis in fecal samples; secondly, it can conduct targeted microecological intervention by supplementing B. uniformis; and thirdly, it can assess the efficacy by monitoring changes in B. uniformis abundance, 3-IBA levels, and cardiac function indicators. This integrated diagnosis and treatment model is conducive to promoting the precision management of chronic heart failure. Attached Figure Description
[0016] 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.
[0017] Figure 1 Bacteroidetes depletion is a metagenomic marker in heart failure patients; Figure 2It was pointed out that Bacteroides depletion is the key bacterial species with the broadest and strongest association with clinical indicators; Figure 3 It was noted that Bacteroides were significantly reduced in the aortic arch constriction heart failure model; Figure 4 It was pointed out that Bacteroides intervention significantly improved cardiac dysfunction in patients with TAC. Figure 5 The study indicated that Bacteroides treatment significantly improved myocardial hypertrophy and intestinal barrier damage in TAC mice. Detailed Implementation
[0018] 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.
[0019] Example 1: Fifty patients with reduced ejection fraction (NYHA class II-IV, EF% ≤ 40%, LVIDd > 55 mm, SBP > 130 mmHg) and 50 healthy controls were included in this study. Fecal samples were collected for metagenomic sequencing. Fecal metagenomic analysis of the heart failure patients and healthy controls revealed a significant decrease in *B. uniformis* abundance in the heart failure patients. Further Spearman correlation analysis showed that *B. uniformis* abundance was significantly correlated with EF% (r = -0.89, p < 0.05), LVIDd (r = 0.85, p < 0.05), LVPW (r = 0.82, p < 0.05), IVS (r = 0.79, p < 0.05), and NYHA functional class (r = 0.91, p < 0.05), making it the most broadly and strongly correlated key bacterial species among all differentially expressed bacterial species. *B. uniformis* was significantly reduced in the feces of the HF group (p < 0.05).
[0020] The above results indicate that *B. uniformis* levels in heart failure patients are not merely fluctuating, but are closely related to disease status and the degree of cardiac function impairment. EF% is an important indicator for evaluating left ventricular systolic function, LVIDd reflects left ventricular end-diastolic diameter, LVPW and IVS reflect ventricular structural changes, and the NYHA functional classification reflects the patient's clinical cardiac function status. *B. uniformis* showed significant correlations with all these core clinical indicators, suggesting that it can reflect the pathological progression of chronic heart failure at the gut microbiota level. Therefore, detecting the abundance of *B. uniformis* in fecal or intestinal contents samples can be used for early risk assessment, disease grading, and treatment monitoring of heart failure.
[0021] Example 2: The study validated the results using a human heart failure microbiota transplantation germ-free pig model. Metagenomic analysis of donor and recipient germ-free pigs with heart failure yielded Venn diagrams (shared microbiota between humans and pigs), PCoA diagrams (β-diversity), and LEfSe differential analysis. These results showed significant depletion of *Bacteroides*, and *B. uniformis* also exhibited a decreasing trend in the human heart failure microbiota transplantation germ-free pig model. These results indicate that the significant decrease in *B. uniformis* in heart failure is not merely an accidental finding in human samples, but rather demonstrates consistency and verifiability in animal models.
[0022] From the inventors' understanding, germ-free pig models can effectively support human gut microbiota and reduce the interference of their own microbial background on experimental results, thus making them suitable for verifying the effects of human heart failure microbiota on the host. *B. uniformis* showed a significant decrease in both human samples and germ-free pig models transplanted with human heart failure microbiota, indicating a high degree of stability in the association between this bacterium and heart failure-related gut microbiota changes, further enhancing the credibility of *B. uniformis* as a diagnostic biomarker and therapeutic target for chronic heart failure.
[0023] Example 3: A mouse model of heart failure was established using aortic arch coarctation (TAC). Three groups were selected: the Sham group, the TAC model group, and the B. uniformis gavage intervention group (1×10⁻⁶). 9The intervention group received CFU / animal / day for 4 consecutive weeks, and the B. uniformis combined with AhR inhibitor (IBA+AHRI) group. Cardiac function was assessed by echocardiography after the intervention. Results showed that the EF% and FS% in the B. uniformis intervention group were significantly higher than those in the model group (p<0.01), the HW / TL and LW / TL ratios were significantly lower (p<0.05), and Collagen-1 protein expression was significantly downregulated. Western blot analysis showed significant recovery of AhR and CYP1A1 protein expression (p<0.05). The above improvements were completely reversed in the AhR inhibitor combination group, confirming that B. uniformis exerts its cardioprotective effect through an AhR-dependent pathway. AB-PAS staining confirmed that the number of intestinal goblet cells recovered and the mucus layer thickness significantly increased after B. uniformis intervention, indicating repair of intestinal barrier function.
[0024] The above-mentioned TAC heart failure mouse experiments demonstrate that *B. uniformis* not only has biomarker value but also practical therapeutic effects. After *B. uniformis* intervention, EF% and FS% significantly increased, indicating improved cardiac contractile function; HW / TL and LW / TL ratios significantly decreased, indicating relief of cardiac hypertrophy and pulmonary congestion-related changes; Collagen-1 protein expression was significantly downregulated, indicating reduced myocardial fibrosis; AhR and CYP1A1 protein expression significantly recovered, indicating that *B. uniformis* can activate the AhR-CYP1A1 signaling pathway; when combined with an AhR inhibitor, the above-mentioned improvements were completely reversed, further confirming that the cardioprotective effect of *B. uniformis* depends on the AhR signaling pathway. AB-PAS staining showed a recovery in the number of intestinal goblet cells and a significant increase in mucus layer thickness, indicating that *B. uniformis* can also repair the intestinal mucus layer and intestinal barrier function, reducing the adverse effects of chronic inflammation and metabolic disorders on the heart from the gut source.
[0025] Example 4: Preparation of *B. uniformis* probiotic formulation. *B. uniformis* was cultured in modified BHI medium under anaerobic conditions until the logarithmic growth phase. The bacterial cells were collected, protected with sterile glycerol (final concentration 20%), and freeze-dried to prepare lyophilized powder. Each capsule contains at least 1 × 10⁻⁶ *B. uniformis*. 9 CFU, with the addition of excipients such as microcrystalline cellulose and low-substituted hydroxypropyl cellulose, is prepared into an enteric-coated capsule formulation to ensure that the activity of the bacterial strain is protected in the acidic environment of the stomach and to effectively colonize the intestine.
[0026] The key focus of this formulation design is to ensure that *B. uniformis*, as a live strain, can safely and stably pass through the acidic environment of the stomach and effectively colonize the intestine. Since the efficacy of *B. uniformis* depends on its colonization in the intestine and its promotion of 3-IBA production, the formulation form needs to fully consider the stability of the live bacteria, acid resistance, storage stability, and intestinal release efficiency. Preparing *B. uniformis* into pharmaceutically acceptable dosage forms such as lyophilized powder, oral capsules, granules, or enteric-coated tablets can improve its clinical feasibility. Enteric-coated capsules, in particular, can reduce damage to the live bacteria from stomach acid, allowing more live bacteria to reach the intestine, thereby better exerting its effects of promoting 3-IBA production, activating the AhR-CYP1A1 signaling pathway, alleviating myocardial fibrosis, and improving cardiac contractile function.
[0027] Example 5: A kit for the auxiliary diagnosis of chronic heart failure was prepared. The kit includes reagents and / or test strips for detecting the abundance of *B. uniformis*, primers, probes, standards, quality controls, and a data analysis module. The test sample can be a stool sample or an intestinal contents sample. By detecting the relative abundance of *B. uniformis* in the sample, and combining this with healthy reference values and clinical indicators such as EF%, LVIDd, LVPW, IVS, and NYHA functional classification, it can be used for early risk assessment, disease grading, and treatment monitoring of chronic heart failure.
[0028] This diagnostic kit provides a convenient, repeatable, and long-term follow-up auxiliary testing method. Compared to cardiac imaging and blood biomarker testing, stool sample collection is relatively easy and can be used to observe changes in the patient's gut microbiota. By detecting the abundance of *B. uniformis*, it is possible to help determine whether a patient has a gut microbiota imbalance associated with heart failure, and further assess the degree of cardiac function impairment in conjunction with clinical indicators. For patients receiving *B. uniformis* probiotic preparations or other heart failure treatment regimens, dynamic monitoring of changes in *B. uniformis* abundance can also evaluate the intervention effect, thereby providing a basis for adjusting individualized treatment plans.
[0029] In summary, all the above embodiments, combined with Figures 1-5As shown, this invention provides the application of *Bacteroides uniformis* in the diagnosis and treatment of chronic heart failure. Through fecal metagenomic sequencing of heart failure patients, validation using a germ-free pig model, and intervention experiments in heart failure mice, this invention found that *B. uniformis* significantly decreased in heart failure, and the degree of decrease was closely related to core clinical indicators such as EF%, LVIDd, and NYHA classification. Further research confirmed that reinfusion of *B. uniformis* can improve myocardial fibrosis and cardiac function through the 3-IBA / AhR / CYP1A1 signaling axis. This invention also demonstrates that in a mouse model of aortic arch coarctation (TAC) heart failure, intervention with *B. uniformis* significantly improved cardiac ejection fraction (EF%) and fractional shortening (FS%), significantly reduced heart weight / tibia length ratio (HW / TL) and lung weight / tibia length ratio (LW / TL), alleviated myocardial fibrosis, and repaired the intestinal mucus layer. When combined with an AhR inhibitor (AHRI), the above protective effects were completely reversed, demonstrating that the cardioprotective effect of *B. uniformis* depends on the AhR signaling pathway.
[0030] Therefore, the core value of this invention lies in linking *B. uniformis* with the diagnosis and treatment of chronic heart failure for the first time, and clarifying its cardioprotective effect through the 3-IBA / AhR / CYP1A1 signaling axis. *B. uniformis* can serve as a microecological biomarker for chronic heart failure, used for early risk assessment, disease grading, and efficacy monitoring; it can also serve as an active ingredient in therapeutic drugs, available in probiotic preparations, oral capsules, granules, lyophilized powders, or enteric-coated tablets for the prevention or treatment of chronic heart failure. Compared with existing technologies, this invention has advantages such as strong targeting, a clear mechanism, definite therapeutic effect, good safety, synergistic use with existing heart failure drugs, and integrated diagnosis and treatment. It can provide new diagnostic and treatment strategies and drug development directions for chronic heart failure, especially hypertension combined with reduced ejection fraction heart failure (HFrEF).
[0031] 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.
[0032] 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
1. The use of a homogeneous Bacteroides in the preparation of drugs for the prevention or treatment of chronic heart failure.
2. The application according to claim 1, characterized in that, The chronic heart failure mentioned refers to either hypertension-associated heart failure with reduced ejection fraction or a subtype of heart failure driven by stress overload.
3. The application according to claim 1, characterized in that, The drug exerts its therapeutic effect through the following mechanism: after colonization by Bacteroides homogeneous, it promotes the synthesis of 3-indolebutyric acid in the intestine and activates the expression of aryl hydrocarbon receptor and its downstream target gene CYP1A1, thereby reducing myocardial fibrosis and improving cardiac contractile function.
4. The application according to claim 1, characterized in that, The drug can also be used in combination with existing heart failure treatments, including one or more combinations of ARNI, beta-blockers, and aldosterone receptor antagonists, to achieve synergistic effects.
5. The application according to claim 1, characterized in that, The drug can be prepared as one of the following: probiotic preparation, oral capsule, granules, lyophilized powder, or enteric-coated tablets.
6. The application according to claim 1, characterized in that, The homogeneous Bacteroides is an active strain that can stably colonize the intestine and promote the production of 3-IBA.
7. The application of uniform Bacteroidetes abundance as a metabolic marker in the preparation of diagnostic kits for chronic heart failure, characterized in that... The kit is used for early risk assessment and disease grading of heart failure by detecting the relative abundance of homogeneous Bacteroides in biological samples.
8. The application according to claim 7, characterized in that, The biological sample is a fecal sample or an intestinal contents sample.
9. The application according to claim 7, characterized in that, A significantly lower abundance of uniform Bacteroides than the healthy reference value suggests a risk of heart failure and is negatively correlated with clinical indicators such as EF%, LVIDd, LVPW, IVS, and NYHA functional classification, which can help assess the degree of cardiac function impairment.