Use of tauroursodeoxycholic acid in preparation of a drug for improving intestinal barrier function and prognosis of patients with sepsis

Abstract

The present application relates to the fields of medicine, biotechnology and clinical critical medicine, and specifically discloses application of tauroursodeoxycholic acid or pharmaceutically acceptable salt, derivative or precursor thereof in preparation of a drug for improving intestinal barrier function and prognosis of a patient with sepsis. The present application discloses for the first time a molecular mechanism of TUDCA for protecting intestinal barrier function by regulating a signal axis of intestinal flora-Coriolic acids-PPARbeta-ILK, and TUDCA significantly improves the integrity of intestinal barrier by restoring intestinal flora balance, inhibiting generation of harmful metabolite Coriolic acids and activating the PPARbeta-ILK signal pathway. In the treatment of sepsis, TUDCA not only helps to repair the intestinal barrier, but also can improve the clinical prognosis of the patient, reduce the level of systemic inflammation, alleviate multiple organ failure caused by sepsis, and improve the survival rate, thereby providing a new strategy for the treatment of sepsis.

Description

Technical Field

[0001] This invention relates to the fields of medicine, biotechnology and clinical critical care medicine, specifically to the use of tauroursodeoxycholic acid in the preparation of drugs for improving intestinal barrier function and prognosis in patients with sepsis. Background Technology

[0002] Sepsis is a systemic inflammatory syndrome caused by a dysregulated response to infection, and is a leading cause of multiple organ dysfunction and high mortality. Clinical studies have shown that the intestine is the earliest and most severely affected organ in sepsis. Disruption of the intestinal barrier not only exacerbates the progression of sepsis but also creates a vicious cycle of infection-inflammation-barrier disruption, further worsening the condition. Therefore, intestinal damage is not only a local manifestation of sepsis but also part of the systemic inflammatory response, severely impacting patient survival. Restoring intestinal homeostasis and protecting the intestinal epithelial barrier are considered crucial strategies for reducing sepsis mortality.

[0003] Currently, clinical treatment for sepsis primarily focuses on anti-infection, fluid resuscitation, and organ function support, but there are no specific drugs targeting intestinal barrier dysfunction. Studies have found that bile acid metabolism disorders are prevalent in sepsis, and bile acids, as important metabolic mediators in host-microbiota interactions, play a crucial role in maintaining intestinal homeostasis. Some studies have shown that tauroursodeoxycholic acid (TUDCA) possesses anti-apoptotic, anti-stress, anti-inflammatory, and epithelial-protective functions and has been used to treat hepatobiliary and neurological diseases. However, the role of TUDCA in sepsis-related intestinal injury has not been systematically studied, and its mechanism of action remains unclear.

[0004] While existing technologies have revealed the protective effects of TUDCA in certain intestinal diseases, these studies have primarily focused on chronic intestinal injury models (such as DSS-induced ulcerative colitis), whereas sepsis-related intestinal injury possesses unique acute characteristics and systemic effects. Sepsis is not merely a localized intestinal injury problem but a systemic inflammatory response syndrome involving multiple organ failure. Disruption of the intestinal barrier promotes bacterial and toxin translocation, further exacerbating the inflammatory response and creating a vicious cycle. Furthermore, the characteristics of intestinal flora imbalance in sepsis differ from those in chronic intestinal diseases, and the involvement of bile acid metabolism disorders, systemic inflammatory responses, and multiple effects on the intestinal barrier in sepsis further complicate treatment.

[0005] While existing research has investigated the role of TUDCA in intestinal barrier protection, most studies focus on its anti-inflammatory, anti-stress, and local effects, lacking in-depth research on its systemic regulation through the gut microbiota-metabolite-receptor-signal axis. Especially in the context of sepsis, the mechanism of action of TUDCA remains unclear, particularly how it repairs intestinal barrier function and improves sepsis-related intestinal damage and clinical prognosis by inhibiting the production of coriolic acids (CA) and activating the peroxisome proliferator-activated receptor β (PPARβ)-integrin-linked kinase (ILK) signaling axis.

[0006] Therefore, current sepsis treatments are insufficient in the following aspects: 1. There is a lack of treatment strategies targeting intestinal barrier dysfunction; current sepsis treatments mainly focus on infection control and supportive therapy; 2. The protective role and mechanism of TUDCA in sepsis have not been systematically elucidated, especially its regulatory effects on gut microbiota and metabolites, and its inhibitory mechanism on inflammatory lipid metabolites, caulic acids (CA); 3. There is a lack of intervention systems based on the "bile acid-microbiota-signaling pathway," and no relevant studies have revealed that TUDCA improves intestinal barrier function and optimizes clinical prognosis in sepsis through this mechanism. Summary of the Invention

[0007] To address the aforementioned issues, this invention proposes an innovative application: utilizing tauroursodeoxycholic acid (TUDCA) to restore intestinal barrier homeostasis, alleviate sepsis-related intestinal damage, and improve patient prognosis by remodeling the gut microbiota structure, inhibiting the production of inflammatory metabolites (CA), and activating peroxisome proliferator-activated receptor β (PPARβ) and its downstream integrin-linked kinase (ILK) signaling pathway. This innovative mechanism not only expands the pharmacological applications of TUDCA but also provides a novel metabolic-signaling intervention approach for the precision treatment of sepsis.

[0008] The specific technical solution adopted in this invention is as follows:

[0009] This invention provides the use of TUDCA or its pharmaceutically acceptable salts, derivatives, or precursors in the preparation of medicaments for improving intestinal barrier function and prognosis in patients with sepsis, wherein the precursor is ursodeoxycholic acid (UDCA).

[0010] Furthermore, the sepsis is a systemic inflammatory response syndrome induced by infection (Sepsis 3.0 diagnostic criteria).

[0011] Furthermore, TUDCA can improve sepsis-related intestinal barrier function and clinical prognosis, focusing on improving pathological conditions such as increased intestinal permeability, decreased epithelial connexin levels, and excessive systemic inflammatory response. The specific mechanisms and manifestations are as follows:

[0012] (1) Intestinal flora regulation: TUDCA can significantly remodel the intestinal flora structure of septic mice and patients, significantly reduce the abundance of inflammatory bacteria such as Pseudomonadota, and restore the intestinal microecological balance. Unlike chronic inflammatory bowel disease, the intestinal flora imbalance in septic patients has acute characteristics, and the mechanism of action of TUDCA in this special context is not addressed in the existing technology;

[0013] (2) Metabolite inhibition: In sepsis, Pseudomonas-derived lipoxygenases catalyze the production of inflammatory metabolites (CA) from linoleic acid. TUDCA significantly inhibits CA synthesis, reducing its negative regulation of host signaling and thus alleviating intestinal barrier damage caused by sepsis. Current technology has not revealed the role of TUDCA in sepsis through this pathway.

[0014] (3) Signal pathway regulation: TUDCA inhibits the antagonistic effect of CA on peroxisome proliferator-activated receptor β (PPARβ), activates the PPARβ–integrin-linked kinase (ILK) signaling axis, and promotes the restoration of expression of tight junction proteins ZO-1, Occludin, and Claudin-1, thereby rebuilding the intestinal barrier structure. The innovation of this mechanism is that TUDCA not only protects the intestinal barrier through anti-inflammatory effects, but also repairs it from a systemic perspective through multi-dimensional signal pathway regulation.

[0015] (4) Systemic anti-inflammatory and clinical improvement: TUDCA treatment can significantly reduce the levels of inflammatory factors such as IL-6, TNF-α, and IL-1β in septic animals and patients, increase the level of anti-inflammatory factor IL-10, reduce the content of inflammatory factors such as serum lactate, PCT, and CRP, reduce the APACHE II score, alleviate the multiple organ failure caused by sepsis, thereby improving the survival rate and effectively improving the clinical prognosis.

[0016] Furthermore, the active ingredient of the drug may be a single component, which is TUDCA or a pharmaceutically acceptable salt, derivative, or precursor thereof.

[0017] Furthermore, the active ingredient of the drug may be a compound composition, wherein the compound composition is a combination of TUDCA or its pharmaceutically acceptable salts, derivatives, prodrugs, and intestinal flora regulators. Wherein:

[0018] The gut microbiota regulators include, but are not limited to, any one or more of the following:

[0019] Probiotics (such as Lactobacillus, Bifidobacterium, etc.) are used to restore the proportion of beneficial bacteria and promote the expression of barrier tight junction proteins.

[0020] Prebiotics or synbiotics (such as inulin and fructooligosaccharides) are used to support the colonization of beneficial bacteria and promote the production of short-chain fatty acids.

[0021] Short-chain fatty acid precursors or receptor agonists can improve intestinal epithelial energy metabolism and the immune microenvironment.

[0022] Fecal microbiota transplantation (FMT) formulations are used to validate or amplify the microbiota-dependent protective effects of TUDCA.

[0023] Combination therapy regimens can be implemented before, during, or after TUDCA treatment to synergistically improve the homeostasis of the "microbiota-metabolism-signaling" network, thereby further improving the efficiency of intestinal barrier repair and clinical prognosis in sepsis patients.

[0024] Furthermore, the dosage forms of the drug include, but are not limited to, oral formulations, injections, enteric-coated tablets, and microemulsions.

[0025] Furthermore, the dosing regimen of the drug is as follows:

[0026] Clinical application: The recommended dose is 12–15 mg / kg / day of TUDCA or its pharmaceutically acceptable salts, derivatives, or prodrugs, taken orally twice daily for 7–10 days.

[0027] Animal model validation: TUDCA or its pharmaceutically acceptable salts, derivatives, or precursors were administered intraperitoneally at a dose of 100 mg / kg once daily for 3 consecutive days, compared with the control group (PBS).

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. Breakthrough Mechanism: This invention reveals for the first time the molecular mechanism by which TUDCA protects intestinal barrier function by regulating the gut microbiota–Coriolic acids–PPARβ–ILK signaling axis. Intestinal damage in sepsis is not limited to the disruption of the intestinal barrier itself, but involves a complex pathological process accompanied by systemic inflammatory responses, microbiota imbalance, and metabolic disorders. TUDCA provides a more comprehensive intervention approach than existing treatments by comprehensively regulating these factors.

[0030] 2. Novel Pharmacological Application: This invention is the first to apply TUDCA to sepsis-related intestinal barrier dysfunction and prognostic improvement. Unlike existing technologies that mainly focus on the application of TUDCA in chronic intestinal diseases (such as ulcerative colitis), this invention focuses on the clinical emergency of acute sepsis, revealing the unique role of TUDCA in the acute phase through microbiota regulation, metabolite inhibition, and signaling pathway activation.

[0031] 3. Systemic Protective Effects: The role of TUDCA in sepsis extends beyond local intestinal protection, encompassing systemic anti-inflammatory effects and synergistic repair of multiple organ functions. By restoring intestinal flora balance, inhibiting the production of harmful metabolites (CA) and activating the PPARβ–ILK signaling pathway, TUDCA significantly improves intestinal barrier integrity, reduces systemic inflammation levels, significantly decreases the levels of inflammatory factors (such as IL-6 and TNF-α), and lowers APACHE II scores, thereby significantly improving the survival rate of sepsis patients.

[0032] 4. High Safety and Translational Potential: TUDCA has a good clinical safety profile and has been approved as a drug or health supplement in China and several other countries, with wide applications in the adjunctive treatment of hepatobiliary and metabolic diseases. As a derivative of UDCA, TUDCA's metabolic pathways and toxicological characteristics in vivo are well-defined, providing a solid foundation for its redevelopment in sepsis-related intestinal barrier dysfunction and ensuring its high clinical translational potential.

[0033] 5. Broad application prospects and industrialization value:

[0034] In the clinical medical field, TUDCA can be used as an adjunct therapy for sepsis patients, in combination with routine anti-infection, fluid resuscitation, and organ support therapy. It improves intestinal barrier function, reduces systemic inflammation, and decreases endotoxin translocation. Due to the acute nature of sepsis-related intestinal injury, early intervention is particularly important. By repairing the intestinal barrier, TUDCA helps alleviate systemic inflammation and significantly improves patient survival and treatment outcomes.

[0035] In the field of drug and formulation development, TUDCA can be developed into single-component formulations (such as injections, capsules, enteric-coated tablets, etc.) as a specific drug for preventing and treating intestinal barrier damage in sepsis. Its unique targeted therapeutic effect makes it an ideal choice for improving intestinal damage in the acute phase of sepsis. TUDCA can also be combined with probiotics, prebiotics, or short-chain fatty acid precursors to form compound formulations to enhance the homeostasis restoration of the intestinal flora and further improve therapeutic efficacy.

[0036] In scientific research and testing applications, TUDCA can serve as a functional bile acid intervention molecule for studying the gut-immune-metabolic axis, helping to explore the interaction between the gut microbiota and the host immune system. Furthermore, by regulating the metabolite coriolic acids (CA) and the PPARβ–ILK signaling axis, TUDCA provides a novel disease monitoring and efficacy evaluation system, supporting the early diagnosis and treatment of acute diseases such as sepsis.

[0037] In the fields of military and emergency medicine, TUDCA can be used to alleviate multi-organ damage following severe trauma, burns, and infection exposure, especially in combat trauma medicine, field infection control, and disaster relief, as an adjunct drug to improve sepsis-related intestinal damage.

[0038] In summary, the TUDCA of this invention has broad application prospects in the fields of sepsis, severe infection, intestinal barrier dysfunction, gut microbiota imbalance, and prevention and treatment of multiple organ failure. By targeting intestinal damage, TUDCA not only provides an innovative intervention strategy for the precision treatment of sepsis, but also offers a new treatment option for improving the prognosis of sepsis patients, demonstrating significant innovation, practicality, and industrialization potential. Attached Figure Description

[0039] Figure 1 : A schematic diagram of the TUDCA mechanism of action in this invention.

[0040] Figure 2 : Technical roadmap of specific embodiments of the present invention.

[0041] Figure 3 Example 1 shows the detection results of tight junction proteins and related inflammation and barrier function indicators in the colon tissue of two sepsis mouse models. In the figure, AB are the Western blot (WB) results and quantitative analysis results of ZO-1, Occludin, and Claudin-1 in colon tissue; C is the HE staining result of colon tissue; D is the immunohistochemical (IHC) result of ZO-1 in colon tissue; E is the immunofluorescence (IF) detection result of Occludin in colon tissue; F is the level of IL-1β, IL-6, TNF-α, and IL-10 in mouse serum; G is the level of α1-antitrypsin (Fecal-α1 antitrypsin) in feces to assess intestinal barrier function.

[0042] Figure 4 Example 1: Combined metabolomics and gut microbiota analysis diagram. A shows the results of metabolomics and quantitative analysis of the metabolite Coriolic acids; B shows the changes in gut microbiota composition and its correlation analysis with the metabolite Coriolic acids.

[0043] Figure 5 The results of PPARβ and ILK protein detection in two sepsis mouse models in Example 1 are shown in the figure. In the figure, AC represents the detection results of the LPS model, including the immunoblotting (A) of PPARβ and ILK in the colon tissue of the LPS model, and the immunohistochemical and immunofluorescence detection results of PPARβ (B) and ILK (C) in the colon tissue; DF represents the detection results of the corresponding CLP model.

[0044] Figure 6 Example 2: Changes in serum and intestinal indicators in clinical sepsis patients. In the figure, A is the flowchart of the clinical trial; B is the SOFA score of the included patients; CL includes changes in Fecal-α1, inflammatory factors (IL-6, TNF-α, IL-1β), anti-inflammatory factors (IL-10), serum lactate, PCT, CRP, WBC levels, and APACHE II score. Detailed Implementation

[0045] Current treatments for sepsis primarily focus on anti-infection and organ support, but lack effective drug interventions targeting intestinal barrier dysfunction. While existing pharmacological studies have suggested that tauroursodeoxycholic acid (TUDCA) possesses anti-inflammatory and anti-apoptotic effects and has been used in chronic intestinal diseases, its protective mechanism in sepsis-related acute intestinal injury remains unclear and differs from its mechanism of action in chronic intestinal diseases. Particularly in the context of sepsis-related intestinal injury, current techniques have not elucidated the following points:

[0046] 1. Does TUDCA participate in the pathological regulation of sepsis by modulating gut microbiota and its metabolites? The gut microbiota imbalance in sepsis is different from that in chronic enteropathies. The acute inflammatory response in sepsis exacerbates the impact of microbiota imbalance. Existing studies have not systematically explored the role of TUDCA in regulating the microbiota in this process.

[0047] 2. Can TUDCA affect inflammatory lipid metabolites (CA)? Sepsis-induced intestinal damage is accompanied by abnormal bile acid metabolism. How TUDCA can reduce the inflammatory response caused by inhibiting the synthesis of CA is a key mechanism not addressed in the prior art.

[0048] 3. Does TUDCA regulate intestinal epithelial barrier integrity through the PPARβ–ILK signaling axis? Currently, research on TUDCA in chronic intestinal injury mainly focuses on its anti-inflammatory effects. However, how TUDCA repairs intestinal barrier function in sepsis by regulating signaling pathways, especially the PPARβ–ILK axis, has not been clearly elucidated.

[0049] This invention demonstrates that TUDCA, by regulating the gut microbiota, inhibiting inflammatory metabolites, and activating the PPARβ–ILK signaling pathway, can target sepsis-related intestinal injury, restore intestinal barrier homeostasis, significantly reduce intestinal damage, and improve systemic inflammatory responses. This mechanism of action represents a lacking targeted therapeutic strategy in current treatments of sepsis-related intestinal injury. Figure 1It demonstrates the pathological chain of "septic state → microbiota imbalance → elevated Coriolic acids (CA) → PPARβ–ILK pathway inhibition → intestinal barrier damage" and the complete action process of "TUDCA intervention → microbiota remodeling → CA inhibition → PPARβ–ILK activation → tight junction protein restoration → barrier repair".

[0050] In the treatment of sepsis, TUDCA not only helps repair the intestinal barrier but also improves patients' clinical prognosis, significantly reduces inflammatory factor levels, and alleviates sepsis-induced multiple organ failure. Therefore, this invention provides a novel treatment strategy by targeting the gut microbiota-metabolite-signaling pathway with TUDCA to repair intestinal barrier damage and improve prognosis in sepsis patients.

[0051] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. The technical approach of the following embodiments is as follows: Figure 2 As shown.

[0052] Example 1: Animal experiment study on the efficacy and mechanism of TUDCA in sepsis

[0053] Animal experimentation and sample testing procedures are as follows Figure 2 As shown, the details are as follows:

[0054] (1) Experimental model

[0055] Two sepsis models were established using male C57BL / 6 mice (20–25 g):

[0056] CLP model: Cervical ligation and perforation (CLP) induces septic sepsis;

[0057] LPS model: Intraperitoneal injection of lipopolysaccharide (LPS, 100 ng / mL, volume ratio 1 mL / 100 g body weight) induces systemic inflammatory response.

[0058] (2) Grouping and administration

[0059] Control group: Normal controls, denoted as SHAM group and Control group, corresponding to CLP model and LPS model respectively;

[0060] Model groups: After induction with CLP or LPS, an equal volume of physiological saline was administered, and these groups were designated as the CLP group and the LPS group.

[0061] TUDCA group (positive control group): Mice in the Control group or SHAM group were administered TUDCA (100 mg / kg) via intraperitoneal injection once daily for 3 consecutive days; TUDCA was dissolved in physiological saline before administration.

[0062] Treatment group: TUDCA (100 mg / kg) was administered intraperitoneally once daily for 3 consecutive days. LPS or CLP induction was performed after the last dose, and the groups were designated as TUDCA_LPS group and TUDCA_CLP group, respectively. TUDCA was administered after being dissolved in physiological saline.

[0063] (3) Testing items and testing methods

[0064] ① Testing items

[0065] Intestinal barrier function indicators: Fecal-α1 antitrypsin level;

[0066] Inflammatory markers: expression levels of IL-1β, IL-6, TNF-α, and IL-10;

[0067] Expression levels of key structural proteins of the intestinal physical barrier: tight junction proteins ZO-1, Occludin, and Claudin-1;

[0068] Signal and metabolic analysis: The relative abundance changes of Coriolic acids, the absolute content of Coriolic acids in colon tissue, and the expression levels of PPARβ and ILK proteins in colon tissue were detected.

[0069] ②Detection method

[0070] After three consecutive days of TUDCA intervention, mice in each experimental group were euthanized under anesthesia 24 hours after LPS or CLP treatment; mice in the control and TUDCA groups were euthanized at the same time point after PBS treatment or SHAM surgery. Peripheral blood, colon tissue, and colonic contents samples were then collected from the mice.

[0071] After peripheral blood samples were centrifuged to separate serum, the serum levels of inflammatory factors (IL-1β, IL-6, TNF-α, IL-10) were detected using the ELISA method.

[0072] Colonic tissue samples were used for histological and molecular-level analysis, including HE staining to observe histopathological changes, immunohistochemistry and immunofluorescence to detect the tissue distribution and expression of tight junction proteins, and Western blotting to detect the expression levels of tight junction proteins. Simultaneously, metabolomics LC-MS analysis of colonic tissue was performed to detect changes in the relative abundance of cordiolic acids, and the absolute content of cordiolic acids was detected by ELISA. Furthermore, Western blot, immunohistochemistry, and immunofluorescence were used to detect the expression levels of PPARβ and ILK proteins in colonic tissue to verify changes in related molecular signals.

[0073] Colonic intestinal contents samples were used for metagenomic sequencing analysis of changes in gut microbiota composition, and fecal α1-antitrypsin (Fecal-α1 antitrypsin) levels were detected using ELISA to assess intestinal barrier function.

[0074] (4) Results

[0075] Figure 3 The results showed the detection results of tight junction proteins and related inflammation and barrier function indicators in colonic tissue. Western blot results showed that in both LPS and CLP sepsis models, TUDCA treatment significantly reversed the downregulation of ZO-1, Occludin, and Claudin-1 expression in the model groups. Figure 3 AB). HE staining results showed that the colonic mucosal structure in the model group was significantly damaged, while the colonic tissue structure was significantly improved after TUDCA intervention. Figure 3 C). Further immunohistochemical and immunofluorescence results showed that TUDCA could restore the continuity of ZO-1 and Occludin distribution in colonic epithelium (C). Figure 3 DE). Meanwhile, ELISA results showed that TUDCA treatment significantly reduced serum IL-1β, IL-6, and TNF-α levels and increased IL-10 levels, while simultaneously decreasing fecal α1-antitrypsin (Fecal-α1 antitrypsin) levels. Figure 3 (FG). The above results collectively indicate that TUDCA can reduce the inflammatory response and maintain the integrity of the intestinal epithelial barrier under sepsis conditions, thereby improving the intestinal barrier structure.

[0076] Figure 4 Results of metabolomics-metagenomics analysis: Figure 4A shows the results of the metabolomics analysis. Metabolomics analysis revealed significant differences in the metabolome between the TUDCA treatment group and the sepsis model group, with VIP value analysis indicating that coriolic acids (CA) were a key differentially expressed metabolite between the two groups. Further analysis showed that TUDCA treatment significantly reduced the relative abundance of CA compared to the model group. ELISA quantification of CA in colon tissue further confirmed that TUDCA intervention significantly reduced the absolute content of CA in both LPS and CLP sepsis mouse models. Figure 4 B represents the results of metagenomic analysis. Metagenomic analysis showed that the overall structure of the gut microbiota in sepsis model mice was significantly disrupted, and TUDCA treatment significantly improved its composition. Further taxonomic analysis indicated that TUDCA treatment significantly inhibited the abnormal increase in Pseudomonas aeruginosa in the sepsis model. Correlation analysis showed a significant positive correlation between CA content in colonic tissue and Pseudomonas aeruginosa abundance. In conclusion, TUDCA can exert a protective effect under sepsis conditions by regulating the gut microbiota-metabolite axis, inhibiting Pseudomonas aeruginosa proliferation, and reducing the accumulation of the inflammation-related metabolite CA.

[0077] Figure 5 This is a validation diagram of the PPARβ–ILK signaling pathway. Western blot results showed that in both LPS and CLP sepsis mouse models, the expression of PPARβ and ILK proteins in the colon tissue of the model groups was significantly downregulated, while the expression levels of both proteins were significantly upregulated after TUDCA intervention. Figure 5 A, D). Immunohistochemical and immunofluorescence results further showed that TUDCA could restore the expression intensity and distribution characteristics of PPARβ and ILK in colon tissue. Figure 5 (BC, 5E-F). The above results indicate that TUDCA can exert a protective effect on colonic tissue under sepsis conditions by activating the PPARβ–ILK signaling pathway.

[0078] Conclusion: TUDCA effectively protects the intestinal barrier in both CLP and LPS sepsis models. The mechanism is related to the regulation of the "microbiota (Pseudomonas)-metabolism (Coriolic acids)-signaling axis (PPARβ-ILK)" and effectively reduces systemic inflammatory response, demonstrating the therapeutic effect of TUDCA on sepsis.

[0079] Example 2: Clinical validation of the efficacy of UDCA, a precursor to TUDCA, in treating sepsis.

[0080] (1) Experimental grouping

[0081] This study employed a prospective observational cohort design, consecutively enrolling hospitalized patients meeting the 3.0 diagnostic criteria for sepsis. Patients were divided into a standard treatment group (UDCA non-users) and a UDCA treatment group (UDCA users) based on whether they received ursodeoxycholic acid (UDCA) treatment. The standard treatment group included 24 patients, and the UDCA treatment group included 7 patients. All patients received the guideline-recommended standard treatment for sepsis; the UDCA treatment group received oral UDCA in addition to standard treatment, at a dose of 12–15 mg / kg / day, administered twice daily for 7 consecutive days; the dosage was determined according to the UDCA drug package insert.

[0082] (2) Explanation of the rationale for choosing UDCA instead of TUDCA

[0083] It should be noted that UDCA was chosen instead of TUDCA as the intervention drug in this clinical study, mainly based on the following considerations:

[0084] On the one hand, existing basic and animal studies have demonstrated that TUDCA has more significant biological effects in anti-inflammation, intestinal barrier protection, and improvement of sepsis-related organ function. On the other hand, UDCA is a major precursor of TUDCA and has been approved by the US FDA for clinical treatment, possessing a clear safety profile and a mature clinical application foundation, which is more conducive to ethical approval and early clinical exploration in sepsis patients. Therefore, this embodiment uses UDCA as a clinical alternative intervention to TUDCA to verify the potential therapeutic value of bile acid-related interventions in sepsis patients and to provide transitional evidence for subsequent clinical research on TUDCA.

[0085] (3) Detection indicators and methods

[0086] On the day of enrollment (day 0), patients were first assessed at baseline. Based on the SOFA score, patients were confirmed to meet the diagnostic criteria for sepsis 3.0, and general clinical data were recorded. At the same time, the APACHE II score was assessed to reflect the severity of the patient's disease.

[0087] On the day of enrollment (day 0), day 4 of treatment, and day 10 of treatment, peripheral blood samples were routinely collected from patients and routine clinical tests were performed, including indicators such as procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC), to dynamically assess the inflammatory status.

[0088] Peripheral blood samples collected at the above time points were centrifuged to obtain serum for further analysis.

[0089] Serum samples were analyzed on days 0, 4 and 10 using ELISA to detect inflammatory markers, including interleukins IL-1β, IL-6, tumor necrosis factor-α (TNF-α) and anti-inflammatory factor IL-10. Serum lactate levels were also measured simultaneously to assess tissue perfusion and metabolic status.

[0090] Anal swab samples were collected simultaneously with peripheral blood samples on days 0, 4, and 10. After processing, the level of α1-antitrypsin (Fecal-α1 antitrypsin) in feces was detected by ELISA to assess the intestinal barrier function.

[0091] In addition, patients' APACHE II scores were reassessed on the enrollment day (day 0) and the follow-up endpoint (day 10) to dynamically evaluate changes in disease severity and treatment response.

[0092] (4) Results

[0093] All enrolled patients met the SOFA 3.0 diagnostic criteria for sepsis on the day of enrollment (Day 0). Figure 6 B), and the day of enrollment was used as the baseline for subsequent dynamic follow-up assessment. Figure 6 The results showed that during the follow-up on days 0, 4 and 10, the UDCA treatment group showed an overall trend of improvement in inflammation, metabolism and intestinal barrier-related indicators, and the efficacy was better than that of the conventional treatment group.

[0094] Regarding the inflammatory response, as the treatment progressed, the levels of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) in the UDCA treatment group gradually decreased from baseline. Figure 6 FH). ELISA results showed that during UDCA treatment, the levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α were significantly lower than baseline, while the level of anti-inflammatory factor IL-10 was correspondingly higher, indicating an improvement in the inflammatory state. Figure 6 IL). Meanwhile, blood lactate levels gradually decreased from baseline, reflecting improvements in tissue perfusion and metabolic status. Figure 6 E).

[0095] In terms of intestinal barrier function assessment, the fecal α1-antitrypsin level in patients in the UDCA treatment group continued to decrease from baseline during the follow-up period, indicating that intestinal barrier function gradually recovered. Figure 6 C).

[0096] Regarding overall disease assessment, with the day of enrollment as the baseline, the APACHE II score change rate of patients in the UDCA treatment group on day 10 showed a decreasing trend, indicating that the severity of the disease gradually improved with the progress of treatment. Figure 6 D).

[0097] The above results indicate that, in patients meeting the SOFA 3.0 diagnostic criteria for sepsis, UDCA intervention was associated with reduced inflammation, improved intestinal barrier function, and an overall trend toward disease remission, suggesting the potential clinical value of bile acid-related interventions in sepsis.

[0098] In summary, this invention not only provides a novel treatment approach for sepsis-related intestinal injury, but also offers a new, feasible, verifiable, and translatable drug application pathway for precision treatment of sepsis through its unique mechanism of action and multidimensional intervention mode, fully demonstrating the innovation and clinical application potential of TUDCA in sepsis.

[0099] This specific embodiment is merely an explanation of the present invention and is not intended to limit the present invention. Any changes made by those skilled in the art after reading the specification of the present invention, as long as they are within the scope of the claims of the present invention, will be protected by patent law.

Claims

1. The use of TUDCA or its pharmaceutically acceptable salts, derivatives, or precursors in the preparation of drugs for improving intestinal barrier function and prognosis in patients with sepsis.

2. The application according to claim 1, characterized in that, Sepsis is a systemic inflammatory response syndrome induced by infection, meeting the Sepsis 3.0 diagnostic criteria.

3. The application according to claim 1, characterized in that, The TUDCA improves intestinal barrier function in sepsis through the gut microbiota-metabolite-PPARβ-ILK signaling pathway, specifically in the following ways: (1) Regulation of gut microbiota: remodeling the gut microbiota structure in the acute phase of sepsis, reducing the abundance of Pseudomonas phylum, and restoring the balance of gut microbiota; (2) Metabolite inhibition: It inhibits the production of inflammatory lipid metabolites, namely coriolic acids, by lipoxygenase from Pseudomonas spp. catalyzing the formation of linoleic acid; (3) Signal pathway regulation: It relieves the antagonistic effect of Coriolic acids on PPARβ, activates the PPARβ-ILK signal axis, promotes the recovery expression of tight junction proteins ZO-1, Occludin, and Claudin-1, thereby rebuilding the intestinal barrier structure.

4. The application according to claim 1, characterized in that, The TUDCA reduces the systemic inflammatory response in patients with sepsis, manifested by decreased levels of inflammatory factors IL-6, TNF-α, and IL-1β, increased levels of anti-inflammatory factor IL-10, and reduced serum lactate, PCT, and CRP levels.

5. The application according to claim 1, characterized in that, The TUDCA improves clinical prognostic indicators in patients with sepsis, reduces APACHE II scores, alleviates sepsis-induced multiple organ failure, and improves survival rates.

6. The application according to claim 1, characterized in that, The active ingredient of the drug is a single component, which is TUDCA or a pharmaceutically acceptable salt, derivative, or precursor thereof.

7. The application according to claim 1, characterized in that, The active ingredient of the drug is a compound composition, which is a combination of TUDCA or its pharmaceutically acceptable salts, derivatives, precursors and intestinal flora regulators.

8. The application according to claim 7, characterized in that, The gut microbiota regulator is selected from at least one of probiotics, prebiotics or synbiotics, short-chain fatty acid precursors or receptor agonists, and FMT-formulations.

9. The application according to claim 1, characterized in that, The dosage form of the drug is an oral preparation, an injection, an enteric-coated tablet, or a microemulsion.

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